Cutaneous Melanoma

MONDO:0005012 Pathograph 6 Show in embeddings browser melanoma

Cutaneous melanoma is a malignant tumor of epidermal melanocytes, driven in most cases by ultraviolet mutagenesis on a MAPK-pathway backbone of BRAF, NRAS, or NF1 alterations. Advanced disease disseminates to distant skin, lymph node, lung, liver, bone, and brain sites, with the metastatic phenotype shaped by transcriptional plasticity, immune escape through PD-1/PD-L1 and related checkpoints, and pronounced brain tropism. The driver-defined subsets are curated in depth in the separate BRAF_V600_Mutant_Melanoma, NRAS_Mutant_Melanoma, and KIT_Mutant_Melanoma entries; this entry carries the shared cutaneous-melanoma biology and the metastatic stage.

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🏷

Classifications

ICD-O Morphology

Harrison's Part

🔗

Mappings

MONDO

MONDO:0005012 cutaneous melanoma

MONDO provides an exact disease term for cutaneous melanoma. This entry was reconstituted from the former Metastatic_Melanoma entry (cancer granularity ladder, design decisions §3a): stage is not a taxon, so the metastatic view now lives in this entry's Metastatic stage.

◆

Subtypes

BRAF V600-Mutant Melanoma

Pointer subtype (design decisions section 3a(d)): curated in depth as the separate BRAF_V600_Mutant_Melanoma entry, which carries the V600E/K driver biology and BRAF/MEK-inhibitor therapy.

NRAS-Mutant Melanoma

Pointer subtype: curated in depth as the separate NRAS_Mutant_Melanoma entry.

KIT-Mutant Melanoma

Pointer subtype: curated in depth as the separate KIT_Mutant_Melanoma entry, which carries its own MONDO term (MONDO:0003865).

Discussions and Knowledge Gaps

What are the primary-tumour mechanisms of cutaneous melanoma - UV mutagenesis, melanocyte transformation, and radial-to-vertical growth-phase progression - and how do they connect to the metastatic mechanisms this entry already models?

KNOWLEDGE GAP OPEN gap_cutaneous_melanoma_primary_tumour_mechanism

Attached to

pathophysiology# stages#Localized

This entry was reconstituted from the former Metastatic_Melanoma entry when the cancer granularity ladder (design decisions section 3a) established that stage is not a taxon and no base cutaneous melanoma entry existed. Every pathophysiology node it inherited is metastasis biology, so the Localized stage currently carries no mechanism content: UV-induced mutagenesis, melanocyte transformation, nevus precursor biology, and the radial-to-vertical growth-phase transition are all absent. The UV exposure is recorded in the environmental section but has no pathophysiology node to act on. Recording this as an open gap keeps the entry honest about what it does and does not yet model, rather than leaving readers to infer coverage from the disease-level description.

⚙

Pathophysiology

MAPK-Driven Metastatic Fitness

Activating BRAF and NRAS mutations, together with NF1 loss, sustain MAPK signaling that promotes proliferation, invasion, therapy resistance, and metastatic competence. These drivers remain central even as melanoma cells transition between proliferative and invasive transcriptional states.

MAPK cascade GO:0000165 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

Downstream

PD-L1-Mediated Immune Escape NF1 loss within this driver set raises PD-L1 expression, coupling the MAPK lesion to checkpoint-mediated escape from cytotoxic T cells.

Invasive Plasticity and Migration Sustained MAPK signalling supports the transition between differentiated and invasive transcriptional states that gives melanoma cells metastatic competence.

Show evidence (1 reference)

PMID:40023845 SUPPORT In Vitro

"Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively."

This supports the dominant mutational architecture underlying metastatic melanoma biology.

Invasive Plasticity and Migration

Melanoma cells toggle between differentiated and invasive states, enabling tissue invasion, vascular entry, and colonization of distant organs. This phenotype is supported by EMT-like programs even in a non-epithelial lineage and is strongly linked to brain and visceral dissemination.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cell migration GO:0016477 ↑ INCREASED positive regulation of cell migration GO:0030335 ↑ INCREASED

Experimental models

Xmrk-activated melanocytes in three-dimensional dermal collagen CELL LINE Reconstitutes the survival barrier a melanocyte meets on entering the dermis, and identifies receptor-driven osteopontin secretion acting through integrin alpha-v beta-3 as the autocrine loop that overcomes it.

Downstream

Brain Metastatic Colonization Invasive, migratory melanoma cells traverse the blood-brain barrier and adapt to the neural microenvironment, the basis of melanoma's marked neurotropism.

PD-L1-Mediated Immune Escape

PD-L1 expression and checkpoint signaling permit metastatic melanoma cells to evade cytotoxic T-cell killing. This immune escape program shapes metastatic site behavior and contributes to heterogeneous responses across cerebral and extracerebral lesions.

negative regulation of immune response GO:0050777 ↑ INCREASED

Show evidence (1 reference)

PMID:25788491 SUPPORT Human Clinical

"Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells."

This directly supports PD-L1-mediated immune evasion in metastatic melanoma.

Brain Metastatic Colonization

Melanoma has marked neurotropism, and brain metastases arise through blood-brain barrier traversal, adaptation to the neural microenvironment, and coordination of targeted and immune resistance programs. Brain lesions are a major cause of neurologic morbidity.

cell migration GO:0016477 ↑ INCREASED

Downstream

Angiogenic Support of Distant Lesions Established cerebral and visceral deposits require angiogenic remodelling and vascular permeability changes to sustain outgrowth.

Show evidence (1 reference)

PMID:40609368 SUPPORT Human Clinical

"Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity."

This supports brain tropism as a defining feature of advanced melanoma.

Angiogenic Support of Distant Lesions

Melanoma metastases require angiogenic remodeling to sustain outgrowth in visceral and cerebral sites, with vascular permeability and local neovascularization supporting both tumor expansion and treatment resistance.

angiogenesis GO:0001525 ↑ INCREASED

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Nervous System 2

Headache FREQUENT HP:0002315

Seizure OCCASIONAL HP:0001250

Constitutional 2

Bone pain OCCASIONAL HP:0002653

Fatigue VERY_FREQUENT HP:0012378

Growth 1

Weight loss FREQUENT HP:0001824

🧬

Genetic Associations

BRAF (Somatic activating mutation)

Gene: BRAF hgnc:1097

NRAS (Somatic activating mutation)

Gene: NRAS hgnc:7989

NF1 (Somatic loss of function)

Gene: NF1 hgnc:7765

PTEN (Somatic loss of function)

Gene: PTEN hgnc:9588

💊

Medical Actions

Ipilimumab Plus Nivolumab Checkpoint Blockade

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: nivolumab NCIT:C68814 ipilimumab CHEBI:231679

Combined CTLA-4 and PD-1 checkpoint blockade is used for metastatic melanoma, including patients with asymptomatic brain metastases, to enhance antitumor T-cell priming and effector activity.

Show evidence (1 reference)

DOI:10.3390/cancers16142559 SUPPORT Human Clinical

"Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM)."

The real-world cohort supports ipilimumab plus nivolumab as a standard systemic immunotherapy option in metastatic melanoma with brain metastases.

🌍

Environmental Factors

Ultraviolet radiation exposure

Ultraviolet mutagenesis drives many primary melanomas and establishes the mutational landscape later selected during metastasis.

Show evidence (1 reference)

PMID:32714859 SUPPORT Human Clinical

"nearly 90% of melanomas are believed to be caused by ultraviolet radiation (UVR), mainly from sunlight"

Establishes UV radiation as the dominant etiologic exposure behind melanoma, the mutational landscape this entry's metastatic nodes act on.

🪜

Stages

Localized

Primary cutaneous melanoma without nodal or distant spread, managed with wide local excision and sentinel-node assessment; most thin melanomas are cured surgically.

Metastatic

Advanced melanoma with dissemination to distant skin, lymph node, lung, liver, bone, and brain sites. Brain tropism is pronounced, and checkpoint blockade and BRAF/MEK-targeted therapy are the systemic mainstays.

This stage carries the content of the former Metastatic_Melanoma entry (cancer granularity ladder, design decisions §3a). Melanoma brain metastases affect up to 60% of advanced melanoma cases.

Show evidence (2 references)

PMID:40609368 SUPPORT Human Clinical

"Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity."

Provides a direct estimate for the burden of brain dissemination in advanced melanoma.

PMID:31343665 SUPPORT Human Clinical

"Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC."

Provides a 5-year survival benchmark for the metastatic stage.

📊

Related Datasets

Whole genome sequencing of primary and metastatic Melanoma cases in an Australian cohort. ega:EGAS00001001552

Melanoma is the fourth most common cancer in Australia and the leading cause of cancer death in young adults. The Australian Melanoma Genome Project (AMGP) is analysing whole genomes from melanomas. We include the results of whole genome sequencing (WGS) for a number of datasets that include cutaneous, acral and mucosal melanoma subtypes.

human

PMID:28467829

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Metastatic Melanoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Gut microbiome modulates response to anti PD1 immunotherapy in metastatic melanoma patients ega:EGAS00001002698

There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R.

human

PMID:29097493

Whole Tumor spatial heterogeneity in metastatic melanoma ega:EGAS00001003292

Heterogeneous inter-tumoral responses, sustained periods of apparent clinical benefit despite lack of objective response to various therapies, and even spontaneous remission are well known within a subpopulation of advanced melanoma patients. The molecular and cellular dynamics facilitating long-term survival remain poorly defined, particularly in the current era ofexposure to multiple potentially active therapies.

human

1H NMR Metabolomics Study of Metastatic Melanoma in C57BL/6J Mouse Spleen metabolomics_workbench:ST000133

mouse METABOLOMICS

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Metastatic Melanoma"). Retrieved 2026-08-02.

A Protein Deep Sequencing Evaluation of Metastatic Melanoma Tissues, fractionated approach massive:MSV000080282

Malignant melanoma has currently the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has previously has very limited possibilities to be cured. Recently, several protein kinase inhibitors and immune modifiers have shown promising results but drug resistance in metastasized melanoma remains a major problem. The need for clinical biomarkers to follow disease progression and treatment effects is high.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Metastatic Melanoma"). Retrieved 2026-08-02.

A Protein Deep Sequencing Evaluation of Metastatic Melanoma Tissues, unfractionated approach massive:MSV000080280

🧫

Experimental Models

Xmrk-activated melanocytes in three-dimensional dermal collagen CELL_LINE

Melanocytes carrying the Xiphophorus melanoma receptor tyrosine kinase Xmrk are embedded in a three-dimensional collagen I gel, the matrix that normally kills melanocytes that leave the epidermis. The assay asks what an activated receptor has to supply for a pigment cell to survive in the dermis, which is the step a melanoma must take to move from radial to vertical growth. Differential display in this system identified osteopontin as the secreted factor that permits it, and osteopontin has since become a prognostic marker in human melanoma. The system is the in-vitro arm of the Xiphophorus melanoma model and is how a fish oncogene was used to name a human invasion mechanism.

Culture

Three-dimensional type I collagen gel reconstituting the dermal environment

Publication

PMID:12183442

Pathograph links

Invasive Plasticity and Migration partially recapitulates fidelity: moderate Reconstitutes the survival barrier a melanocyte meets on entering the dermis, and identifies receptor-driven osteopontin secretion acting through integrin alpha-v beta-3 as the autocrine loop that overcomes it.

Limitations: A three-dimensional gel is not a vascularized dermis and reports survival and spreading rather than true invasion, vascular entry, or distant colonization, so it covers only the first step of the node. The driving receptor is the fish Xmrk oncogene rather than a human melanoma driver, and the assay carries no immune or stromal compartment. The responding cell is a cultured melanocyte line rather than a human melanocyte in situ, so any species difference between that host cell and human melanocytes is uncontrolled here and is a second translational gap alongside the fish receptor. Treat it as evidence for the osteopontin mechanism, not for metastatic competence.

Readouts

Melanocyte survival and spreading in collagen I with and without osteopontin

Adhesion, spreading, and apoptosis of melanocytes in three-dimensional collagen gels, scored against osteopontin availability in the medium.

Direction: RESTORED

Interpretation: Osteopontin is sufficient to rescue melanocytes from matrix-induced apoptosis and necessary for the receptor-driven rescue, which is what identifies it as the effector of dermal survival.

Show evidence (1 reference)

PMID:12183442 SUPPORT In Vitro

"Addition of exogenous OPN allowed melanocytes to adhere, spread, and survive in three-dimensional collagen gels, whereas in the absence of OPN, the cells underwent apoptosis."

Reports the add-back experiment that grounds this readout in both directions.

Show evidence (2 references)

PMID:12183442 SUPPORT In Vitro

"In melanocytes, expression of the secreted adhesion protein OPN was up-regulated by the melanoma-inducing receptor tyrosine kinase Xmrk"

Links the fish melanoma oncogene to induction of the secreted factor that licenses melanocyte survival in dermal matrix.

+ 1 more reference

Findings

Osteopontin secreted downstream of Xmrk acts through integrin alpha-v beta-3 to sustain melanocytes in dermal collagen, identifying an autocrine growth-factor-receptor-to-integrin crosstalk that permits dermal invasion.

"Activation of both receptors triggered survival of melanocytes in three-dimensional dermal collagen gels."

{ }

Source YAML

click to show

name: Cutaneous Melanoma
creation_date: '2026-03-28T21:05:00Z'
description: >-
  Cutaneous melanoma is a malignant tumor of epidermal melanocytes, driven in
  most cases by ultraviolet mutagenesis on a MAPK-pathway backbone of BRAF,
  NRAS, or NF1 alterations. Advanced disease disseminates to distant skin,
  lymph node, lung, liver, bone, and brain sites, with the metastatic
  phenotype shaped by transcriptional plasticity, immune escape through
  PD-1/PD-L1 and related checkpoints, and pronounced brain tropism. The
  driver-defined subsets are curated in depth in the separate
  BRAF_V600_Mutant_Melanoma, NRAS_Mutant_Melanoma, and KIT_Mutant_Melanoma
  entries; this entry carries the shared cutaneous-melanoma biology and the
  metastatic stage.
categories:
- Skin Cancer
- Solid Tumor
parents:
- melanoma
disease_term:
  preferred_term: cutaneous melanoma
  term:
    id: MONDO:0005012
    label: cutaneous melanoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005012
      label: cutaneous melanoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO provides an exact disease term for cutaneous melanoma. This entry
      was reconstituted from the former Metastatic_Melanoma entry (cancer
      granularity ladder, design decisions §3a): stage is not a taxon, so the
      metastatic view now lives in this entry's Metastatic stage.
classifications:
  icdo_morphology:
    classification_value: Melanoma
    notes: >-
      Derived from this entry's disease term MONDO:0005012 (cutaneous melanoma).
      Its NCIT cross-reference NCIT:C3510 (Cutaneous Melanoma) is a descendant of
      NCIT:C3224 (Melanoma), the term this enum value is bound to. The MONDO
      parent MONDO:0005105 (melanoma) additionally carries the cross-reference
      ICDO:8720/3. Metastatic disease does not change the morphology axis, which
      records the histological type of the primary tumor.
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      Melanoma is managed as a solid-tumor oncology problem
      (checkpoint blockade, BRAF/MEK-targeted therapy).
has_subtypes:
- name: BRAF V600-mutant
  display_name: BRAF V600-Mutant Melanoma
  description: >-
    Pointer subtype (design decisions section 3a(d)): curated in depth as the
    separate BRAF_V600_Mutant_Melanoma entry, which carries the V600E/K driver
    biology and BRAF/MEK-inhibitor therapy.
- name: NRAS-mutant
  display_name: NRAS-Mutant Melanoma
  description: >-
    Pointer subtype: curated in depth as the separate NRAS_Mutant_Melanoma
    entry.
- name: KIT-mutant
  display_name: KIT-Mutant Melanoma
  description: >-
    Pointer subtype: curated in depth as the separate KIT_Mutant_Melanoma
    entry, which carries its own MONDO term (MONDO:0003865).
stages:
- name: Localized
  description: >-
    Primary cutaneous melanoma without nodal or distant spread, managed with
    wide local excision and sentinel-node assessment; most thin melanomas are
    cured surgically.
- name: Metastatic
  description: >-
    Advanced melanoma with dissemination to distant skin, lymph node, lung,
    liver, bone, and brain sites. Brain tropism is pronounced, and checkpoint
    blockade and BRAF/MEK-targeted therapy are the systemic mainstays.
  notes: >-
    This stage carries the content of the former Metastatic_Melanoma entry
    (cancer granularity ladder, design decisions §3a). Melanoma brain
    metastases affect up to 60% of advanced melanoma cases.
  evidence:
  - reference: PMID:40609368
    reference_title: "Evolving treatment paradigms for melanoma brain metastases: A systematic review of current modalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity.
    explanation: Provides a direct estimate for the burden of brain dissemination in advanced melanoma.
  - reference: PMID:31343665
    reference_title: "Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC.
    explanation: Provides a 5-year survival benchmark for the metastatic stage.

pathophysiology:
- name: MAPK-Driven Metastatic Fitness
  description: >-
    Activating BRAF and NRAS mutations, together with NF1 loss, sustain MAPK signaling
    that promotes proliferation, invasion, therapy resistance, and metastatic competence.
    These drivers remain central even as melanoma cells transition between proliferative
    and invasive transcriptional states.
  evidence:
  - reference: PMID:40023845
    reference_title: "The NF1 tumor suppressor regulates PD-L1 and immune evasion in melanoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively.
    explanation: This supports the dominant mutational architecture underlying metastatic melanoma biology.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: PD-L1-Mediated Immune Escape
    description: >-
      NF1 loss within this driver set raises PD-L1 expression, coupling the MAPK
      lesion to checkpoint-mediated escape from cytotoxic T cells.
  - target: Invasive Plasticity and Migration
    description: >-
      Sustained MAPK signalling supports the transition between differentiated and
      invasive transcriptional states that gives melanoma cells metastatic
      competence.
- name: Invasive Plasticity and Migration
  conforms_to: "invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation"
  description: >-
    Melanoma cells toggle between differentiated and invasive states, enabling tissue
    invasion, vascular entry, and colonization of distant organs. This phenotype is
    supported by EMT-like programs even in a non-epithelial lineage and is strongly
    linked
    to brain and visceral dissemination.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
  downstream:
  - target: Brain Metastatic Colonization
    description: >-
      Invasive, migratory melanoma cells traverse the blood-brain barrier and adapt
      to the neural microenvironment, the basis of melanoma's marked neurotropism.
- name: PD-L1-Mediated Immune Escape
  description: >-
    PD-L1 expression and checkpoint signaling permit metastatic melanoma cells to
    evade
    cytotoxic T-cell killing. This immune escape program shapes metastatic site behavior
    and contributes to heterogeneous responses across cerebral and extracerebral lesions.
  evidence:
  - reference: PMID:25788491
    reference_title: "Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells.
    explanation: This directly supports PD-L1-mediated immune evasion in metastatic melanoma.
  biological_processes:
  - preferred_term: negative regulation of immune response
    modifier: INCREASED
    term:
      id: GO:0050777
      label: negative regulation of immune response
- name: Brain Metastatic Colonization
  conforms_to: "invasion_and_metastasis#Metastatic Colonization"
  description: >-
    Melanoma has marked neurotropism, and brain metastases arise through blood-brain
    barrier
    traversal, adaptation to the neural microenvironment, and coordination of targeted
    and
    immune resistance programs. Brain lesions are a major cause of neurologic morbidity.
  evidence:
  - reference: PMID:40609368
    reference_title: "Evolving treatment paradigms for melanoma brain metastases: A systematic review of current modalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity.
    explanation: This supports brain tropism as a defining feature of advanced melanoma.
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  downstream:
  - target: Angiogenic Support of Distant Lesions
    description: >-
      Established cerebral and visceral deposits require angiogenic remodelling and
      vascular permeability changes to sustain outgrowth.
- name: Angiogenic Support of Distant Lesions
  description: >-
    Melanoma metastases require angiogenic remodeling to sustain outgrowth in visceral
    and
    cerebral sites, with vascular permeability and local neovascularization supporting
    both
    tumor expansion and treatment resistance.
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
phenotypes:
- category: Neurologic
  name: Headache
  frequency: FREQUENT
  description: Headache is common in melanoma brain metastases and often reflects edema or intracranial mass effect.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Neurologic
  name: Seizure
  frequency: OCCASIONAL
  description: Seizures occur with cortical brain metastases and hemorrhagic lesions.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
- category: Musculoskeletal
  name: Bone pain
  frequency: OCCASIONAL
  description: Bone metastases cause focal pain and skeletal fragility.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
- category: Constitutional
  name: Weight loss
  frequency: FREQUENT
  description: Progressive metastatic melanoma often causes systemic weight loss and cachexia.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Constitutional
  name: Fatigue
  frequency: VERY_FREQUENT
  description: Fatigue reflects inflammatory burden, treatment effects, and advanced disease.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
genetic:
- name: BRAF
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Somatic activating mutation
  notes: BRAF V600 alterations are major drivers of metastatic melanoma and support dependence on MAPK signaling.
- name: NRAS
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  association: Somatic activating mutation
  notes: NRAS mutations promote MAPK and PI3K pathway activation and contribute to invasive plasticity.
- name: NF1
  gene_term:
    preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  association: Somatic loss of function
  notes: NF1 loss releases RAS signaling and can increase PD-L1 expression and immune evasion.
- name: PTEN
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  association: Somatic loss of function
  notes: PTEN loss augments PI3K-AKT signaling and is associated with aggressive metastatic behavior.
environmental:
- name: Ultraviolet radiation exposure
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  notes: Ultraviolet mutagenesis drives many primary melanomas and establishes the mutational landscape later selected during metastasis.
  evidence:
  - reference: PMID:32714859
    reference_title: "Ultraviolet Radiation and Melanomagenesis: From Mechanism to Immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly 90% of melanomas are believed to be caused by ultraviolet radiation (UVR), mainly from sunlight"
    explanation: Establishes UV radiation as the dominant etiologic exposure behind melanoma, the mutational landscape this entry's metastatic nodes act on.
notes: >-
  Requested NCIT cross-reference: NCIT:C8925 (for the metastatic stage;
  NCIT:C3510 is cutaneous melanoma). Brain metastasis, PD-L1-mediated immune
  escape, and BRAF/NRAS/NF1 MAPK signaling are dominant features of the
  metastatic state, modeled on this entry's pathophysiology nodes.
treatments:
- name: Ipilimumab Plus Nivolumab Checkpoint Blockade
  description: Combined CTLA-4 and PD-1 checkpoint blockade is used for metastatic melanoma, including patients with asymptomatic brain metastases, to enhance antitumor T-cell priming and effector activity.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
    - preferred_term: ipilimumab
      term:
        id: CHEBI:231679
        label: ipilimumab
  evidence:
  - reference: DOI:10.3390/cancers16142559
    reference_title: Efficacy of Ipilimumab and Nivolumab in Patients with Melanoma and Brain Metastases—A Danish Real-World Cohort
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM).
    explanation: The real-world cohort supports ipilimumab plus nivolumab as a standard systemic immunotherapy option in metastatic melanoma with brain metastases.
references:
- reference: DOI:10.1007/s11060-025-04951-z
  title: Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice
    supporting_text: Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice
- reference: DOI:10.1080/14737159.2024.2347484
  title: 'Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: 'Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios'
    supporting_text: 'Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios'
- reference: DOI:10.1093/noajnl/vdae090.044
  title: IMUN-05 PHASE II STUDY OF NIVOLUMAB (NIVO) IN COMBINATION WITH RELATLIMAB (RELA) IN PATIENTS WITH ACTIVE MELANOMA BRAIN METASTASES (MBM)
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases.
    supporting_text: More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases.
    evidence:
    - reference: DOI:10.1093/noajnl/vdae090.044
      reference_title: IMUN-05 PHASE II STUDY OF NIVOLUMAB (NIVO) IN COMBINATION WITH RELATLIMAB (RELA) IN PATIENTS WITH ACTIVE MELANOMA BRAIN METASTASES (MBM)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.1097/cm9.0000000000003416
  title: Recent global patterns in skin cancer incidence, mortality, and prevalence
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases.
    supporting_text: Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases.
    evidence:
    - reference: DOI:10.1097/cm9.0000000000003416
      reference_title: Recent global patterns in skin cancer incidence, mortality, and prevalence
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.1097/cmr.0000000000000959
  title: Global trends in cutaneous malignant melanoma incidence and mortality
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries.
    supporting_text: Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries.
    evidence:
    - reference: DOI:10.1097/cmr.0000000000000959
      reference_title: Global trends in cutaneous malignant melanoma incidence and mortality
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.1186/s12885-024-12426-z
  title: Patterns and trends in melanoma mortality in the United States, 1999–2020
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades.
    supporting_text: Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades.
    evidence:
    - reference: DOI:10.1186/s12885-024-12426-z
      reference_title: Patterns and trends in melanoma mortality in the United States, 1999–2020
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.1371/journal.pgen.1007589
  title: Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
    supporting_text: Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
- reference: DOI:10.20517/cdr.2023.150
  title: Current knowledge about immunotherapy resistance for melanoma and potential predictive and prognostic biomarkers
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma.
    supporting_text: Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma.
    evidence:
    - reference: DOI:10.20517/cdr.2023.150
      reference_title: Current knowledge about immunotherapy resistance for melanoma and potential predictive and prognostic biomarkers
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.20517/cdr.2024.54
  title: Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years.
    supporting_text: Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years.
    evidence:
    - reference: DOI:10.20517/cdr.2024.54
      reference_title: Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3389/fimmu.2024.1520441
  title: 'The prognostic value of circulating tumor DNA in malignant melanoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load.
    supporting_text: Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load.
    evidence:
    - reference: DOI:10.3389/fimmu.2024.1520441
      reference_title: 'The prognostic value of circulating tumor DNA in malignant melanoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3389/fonc.2024.1512942
  title: Global, regional, and national burden of cutaneous malignant melanoma from 1990 to 2021 and prediction to 2045
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Cutaneous Malignant Melanoma (CMM) is a significant global health challenge.
    supporting_text: Cutaneous Malignant Melanoma (CMM) is a significant global health challenge.
    evidence:
    - reference: DOI:10.3389/fonc.2024.1512942
      reference_title: Global, regional, and national burden of cutaneous malignant melanoma from 1990 to 2021 and prediction to 2045
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Cutaneous Malignant Melanoma (CMM) is a significant global health challenge.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/biom15020269
  title: Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms.
    supporting_text: Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms.
    evidence:
    - reference: DOI:10.3390/biom15020269
      reference_title: Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/biomedicines13010225
  title: Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes.
    supporting_text: Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes.
    evidence:
    - reference: DOI:10.3390/biomedicines13010225
      reference_title: Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cancers15123224
  title: New Approaches to Targeted Therapy in Melanoma
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies.
    supporting_text: It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies.
    evidence:
    - reference: DOI:10.3390/cancers15123224
      reference_title: New Approaches to Targeted Therapy in Melanoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cancers16010101
  title: 'Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma.
    supporting_text: The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma.
    evidence:
    - reference: DOI:10.3390/cancers16010101
      reference_title: 'Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cancers16081571
  title: 'Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs.
    supporting_text: Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs.
    evidence:
    - reference: DOI:10.3390/cancers16081571
      reference_title: 'Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cancers16142559
  title: Efficacy of Ipilimumab and Nivolumab in Patients with Melanoma and Brain Metastases—A Danish Real-World Cohort
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM).
    supporting_text: Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM).
    evidence:
    - reference: DOI:10.3390/cancers16142559
      reference_title: Efficacy of Ipilimumab and Nivolumab in Patients with Melanoma and Brain Metastases—A Danish Real-World Cohort
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM).
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cancers18030382
  title: 'Drug Therapy for Melanoma: Current Updates and Future Prospects'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies.
    supporting_text: Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies.
    evidence:
    - reference: DOI:10.3390/cancers18030382
      reference_title: 'Drug Therapy for Melanoma: Current Updates and Future Prospects'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/cells13161383
  title: Molecular Susceptibility and Treatment Challenges in Melanoma
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors.
    supporting_text: Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors.
    evidence:
    - reference: DOI:10.3390/cells13161383
      reference_title: Molecular Susceptibility and Treatment Challenges in Melanoma
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3390/ijms251810120
  title: 'Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?'
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma.
    supporting_text: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma.
    evidence:
    - reference: DOI:10.3390/ijms251810120
      reference_title: 'Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma.
      explanation: Deep research cited this publication as relevant literature for Metastatic Melanoma.
- reference: DOI:10.3892/mi.2024.137
  title: Immune checkpoint inhibitors in metastatic melanoma therapy (Review)
  found_in:
  - Metastatic_Melanoma-deep-research-falcon.md
  findings:
  - statement: Immune checkpoint inhibitors in metastatic melanoma therapy (Review)
    supporting_text: Immune checkpoint inhibitors in metastatic melanoma therapy (Review)
experimental_models:
- name: Xmrk-activated melanocytes in three-dimensional dermal collagen
  experimental_model_type: CELL_LINE
  culture_system: Three-dimensional type I collagen gel reconstituting the dermal environment
  publication: PMID:12183442
  description: >-
    Melanocytes carrying the Xiphophorus melanoma receptor tyrosine kinase Xmrk
    are embedded in a three-dimensional collagen I gel, the matrix that normally
    kills melanocytes that leave the epidermis. The assay asks what an activated
    receptor has to supply for a pigment cell to survive in the dermis, which is
    the step a melanoma must take to move from radial to vertical growth.
    Differential display in this system identified osteopontin as the secreted
    factor that permits it, and osteopontin has since become a prognostic marker
    in human melanoma. The system is the in-vitro arm of the Xiphophorus melanoma
    model and is how a fish oncogene was used to name a human invasion mechanism.
  modeled_mechanisms:
  - target: Invasive Plasticity and Migration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reconstitutes the survival barrier a melanocyte meets on entering the
      dermis, and identifies receptor-driven osteopontin secretion acting through
      integrin alpha-v beta-3 as the autocrine loop that overcomes it.
    limitations: >-
      A three-dimensional gel is not a vascularized dermis and reports survival
      and spreading rather than true invasion, vascular entry, or distant
      colonization, so it covers only the first step of the node. The driving
      receptor is the fish Xmrk oncogene rather than a human melanoma driver,
      and the assay carries no immune or stromal compartment. The responding
      cell is a cultured melanocyte line rather than a human melanocyte in situ,
      so any species difference between that host cell and human melanocytes is
      uncontrolled here and is a second translational gap alongside the fish
      receptor. Treat it as evidence for the osteopontin mechanism, not for
      metastatic competence.
    readouts:
    - name: Melanocyte survival and spreading in collagen I with and without osteopontin
      target: Invasive Plasticity and Migration
      description: >-
        Adhesion, spreading, and apoptosis of melanocytes in three-dimensional
        collagen gels, scored against osteopontin availability in the medium.
      direction: RESTORED
      interpretation: >-
        Osteopontin is sufficient to rescue melanocytes from matrix-induced
        apoptosis and necessary for the receptor-driven rescue, which is what
        identifies it as the effector of dermal survival.
      evidence:
      - reference: PMID:12183442
        reference_title: Autocrine stimulation by osteopontin contributes to antiapoptotic signalling of melanocytes in dermal collagen.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Addition of exogenous OPN allowed melanocytes to adhere, spread, and survive in three-dimensional collagen gels, whereas in the absence of OPN, the cells underwent apoptosis.
        explanation: Reports the add-back experiment that grounds this readout in both directions.
    evidence:
    - reference: PMID:12183442
      reference_title: Autocrine stimulation by osteopontin contributes to antiapoptotic signalling of melanocytes in dermal collagen.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In melanocytes, expression of the secreted adhesion protein OPN was up-regulated by the melanoma-inducing receptor tyrosine kinase Xmrk
      explanation: >-
        Links the fish melanoma oncogene to induction of the secreted factor that
        licenses melanocyte survival in dermal matrix.
    - reference: PMID:38299666
      reference_title: Validity of Xiphophorus fish as models for human disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: the secreted glycoprotein osteopontin was first identified in Xiphophorus melanoma as a key factor for the transition from radial to vertical growth
      explanation: >-
        States that the radial-to-vertical transition factor described by this
        node was first identified through the Xiphophorus system.
  findings:
  - statement: >-
      Osteopontin secreted downstream of Xmrk acts through integrin alpha-v
      beta-3 to sustain melanocytes in dermal collagen, identifying an autocrine
      growth-factor-receptor-to-integrin crosstalk that permits dermal invasion.
    supporting_text: Activation of both receptors triggered survival of melanocytes in three-dimensional dermal collagen gels.
datasets:
- accession: ega:EGAS00001001552
  title: Whole genome sequencing of primary and metastatic Melanoma cases in an Australian cohort.
  description: Melanoma is the fourth most common cancer in Australia and the leading cause of cancer death in young adults. The Australian Melanoma Genome Project (AMGP) is analysing whole genomes from melanomas. We include the results of whole genome sequencing (WGS) for a number of datasets that include cutaneous, acral and mucosal melanoma subtypes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28467829
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Melanoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001002698
  title: Gut microbiome modulates response to anti PD1 immunotherapy in metastatic melanoma patients
  description: There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:29097493
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Melanoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003292
  title: Whole Tumor spatial heterogeneity in metastatic melanoma
  description: Heterogeneous inter-tumoral responses, sustained periods of apparent clinical benefit despite lack of objective response to various therapies, and even spontaneous remission are well known within a subpopulation of advanced melanoma patients. The molecular and cellular dynamics facilitating long-term survival remain poorly defined, particularly in the current era ofexposure to multiple potentially active therapies.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Melanoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST000133
  title: 1H NMR Metabolomics Study of Metastatic Melanoma in C57BL/6J Mouse Spleen
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Metastatic Melanoma"). Retrieved 2026-08-02.
- accession: massive:MSV000080282
  title: A Protein Deep Sequencing Evaluation of Metastatic Melanoma Tissues, fractionated approach
  description: Malignant melanoma has currently the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has previously has very limited possibilities to be cured. Recently, several protein kinase inhibitors and immune modifiers have shown promising results but drug resistance in metastasized melanoma remains a major problem. The need for clinical biomarkers to follow disease progression and treatment effects is high.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Metastatic Melanoma"). Retrieved 2026-08-02.
- accession: massive:MSV000080280
  title: A Protein Deep Sequencing Evaluation of Metastatic Melanoma Tissues, unfractionated approach
  description: Malignant melanoma has currently the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has previously has very limited possibilities to be cured. Recently, several protein kinase inhibitors and immune modifiers have shown promising results but drug resistance in metastasized melanoma remains a major problem. The need for clinical biomarkers to follow disease progression and treatment effects is high.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Metastatic Melanoma"). Retrieved 2026-08-02.
discussions:
- discussion_id: gap_cutaneous_melanoma_primary_tumour_mechanism
  prompt: >-
    What are the primary-tumour mechanisms of cutaneous melanoma - UV mutagenesis,
    melanocyte transformation, and radial-to-vertical growth-phase progression - and
    how do they connect to the metastatic mechanisms this entry already models?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#
  - stages#Localized
  rationale: >-
    This entry was reconstituted from the former Metastatic_Melanoma entry when the
    cancer granularity ladder (design decisions section 3a) established that stage is
    not a taxon and no base cutaneous melanoma entry existed. Every pathophysiology
    node it inherited is metastasis biology, so the Localized stage currently carries
    no mechanism content: UV-induced mutagenesis, melanocyte transformation, nevus
    precursor biology, and the radial-to-vertical growth-phase transition are all
    absent. The UV exposure is recorded in the environmental section but has no
    pathophysiology node to act on. Recording this as an open gap keeps the entry
    honest about what it does and does not yet model, rather than leaving readers to
    infer coverage from the disease-level description.

📚

References & Deep Research

References

DOI:10.1007/s11060-025-04951-z

Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice

1 finding

Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice

"Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice"

DOI:10.1080/14737159.2024.2347484

Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios

1 finding

Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios

"Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios"

DOI:10.1093/noajnl/vdae090.044

IMUN-05 PHASE II STUDY OF NIVOLUMAB (NIVO) IN COMBINATION WITH RELATLIMAB (RELA) IN PATIENTS WITH ACTIVE MELANOMA BRAIN METASTASES (MBM)

1 finding

More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases.

"More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases."

Show evidence (1 reference)

DOI:10.1093/noajnl/vdae090.044 SUPPORT Human Clinical

"More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.1097/cm9.0000000000003416

Recent global patterns in skin cancer incidence, mortality, and prevalence

1 finding

Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases.

"Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases."

Show evidence (1 reference)

DOI:10.1097/cm9.0000000000003416 SUPPORT Human Clinical

"Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.1097/cmr.0000000000000959

Global trends in cutaneous malignant melanoma incidence and mortality

1 finding

Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries.

"Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries."

Show evidence (1 reference)

DOI:10.1097/cmr.0000000000000959 SUPPORT Human Clinical

"Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.1186/s12885-024-12426-z

Patterns and trends in melanoma mortality in the United States, 1999–2020

1 finding

Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades.

"Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades."

Show evidence (1 reference)

DOI:10.1186/s12885-024-12426-z SUPPORT Human Clinical

"Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.1371/journal.pgen.1007589

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis

1 finding

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis

"Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis"

DOI:10.20517/cdr.2023.150

Current knowledge about immunotherapy resistance for melanoma and potential predictive and prognostic biomarkers

1 finding

Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma.

"Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma."

Show evidence (1 reference)

DOI:10.20517/cdr.2023.150 SUPPORT Human Clinical

"Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.20517/cdr.2024.54

Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma

1 finding

Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years.

"Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years."

Show evidence (1 reference)

DOI:10.20517/cdr.2024.54 SUPPORT Human Clinical

"Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3389/fimmu.2024.1520441

The prognostic value of circulating tumor DNA in malignant melanoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

1 finding

Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load.

"Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load."

Show evidence (1 reference)

DOI:10.3389/fimmu.2024.1520441 SUPPORT Other

"Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3389/fonc.2024.1512942

Global, regional, and national burden of cutaneous malignant melanoma from 1990 to 2021 and prediction to 2045

1 finding

Cutaneous Malignant Melanoma (CMM) is a significant global health challenge.

"Cutaneous Malignant Melanoma (CMM) is a significant global health challenge."

Show evidence (1 reference)

DOI:10.3389/fonc.2024.1512942 SUPPORT Computational

"Cutaneous Malignant Melanoma (CMM) is a significant global health challenge."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/biom15020269

Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It

1 finding

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms.

"Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms."

Show evidence (1 reference)

DOI:10.3390/biom15020269 SUPPORT Other

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/biomedicines13010225

Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma

1 finding

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes.

"Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes."

Show evidence (1 reference)

DOI:10.3390/biomedicines13010225 SUPPORT Human Clinical

"Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cancers15123224

New Approaches to Targeted Therapy in Melanoma

1 finding

It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies.

"It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies."

Show evidence (1 reference)

DOI:10.3390/cancers15123224 SUPPORT Human Clinical

"It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cancers16010101

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

1 finding

The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma.

"The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma."

Show evidence (1 reference)

DOI:10.3390/cancers16010101 SUPPORT Human Clinical

"The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cancers16081571

Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance

1 finding

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs.

"Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs."

Show evidence (1 reference)

DOI:10.3390/cancers16081571 SUPPORT Other

"Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cancers16142559

Efficacy of Ipilimumab and Nivolumab in Patients with Melanoma and Brain Metastases—A Danish Real-World Cohort

1 finding

Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM).

"Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM)."

Show evidence (1 reference)

DOI:10.3390/cancers16142559 SUPPORT Human Clinical

"Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM)."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cancers18030382

Drug Therapy for Melanoma: Current Updates and Future Prospects

1 finding

Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies.

"Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies."

Show evidence (1 reference)

DOI:10.3390/cancers18030382 SUPPORT Other

"Melanoma was once considered ‘incurable’; however, drug therapy for the condition has dramatically transformed with the advent of immune checkpoint inhibitors and molecular targeted therapies."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/cells13161383

Molecular Susceptibility and Treatment Challenges in Melanoma

1 finding

Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors.

"Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors."

Show evidence (1 reference)

DOI:10.3390/cells13161383 SUPPORT Other

"Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3390/ijms251810120

Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?

1 finding

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma.

"Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma."

Show evidence (1 reference)

DOI:10.3390/ijms251810120 SUPPORT Human Clinical

"Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma."

Deep research cited this publication as relevant literature for Metastatic Melanoma.

DOI:10.3892/mi.2024.137

Immune checkpoint inhibitors in metastatic melanoma therapy (Review)

1 finding

Immune checkpoint inhibitors in metastatic melanoma therapy (Review)

"Immune checkpoint inhibitors in metastatic melanoma therapy (Review)"

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