Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Establishing causal links between genetic alterations and cancer phenotypes is difficult.
• Melanoma is driven by mutations in key signaling pathways.

Purpose of the Study:

• To create genetically distinct human melanoma models.
• To connect specific genotypes to malignant phenotypes and expression programs.

Main Methods:

• Sequential introduction of mutations into healthy human melanocytes.
• Development of nine distinct cellular models of melanoma.
• In vitro and in vivo analysis of cell expression, immortality, malignancy, growth, pigmentation, metastasis, and histopathology.

Main Results:

• Genetically distinct melanoma models were established.
• Mutant genotypes were linked to specific malignant phenotypes and altered tumor microenvironments.
• Models showed genotype-associated expression programs similar to patient melanomas.
• Deep learning analysis revealed partial recapitulation of genotype-associated histopathology.

Conclusions:

• Progressive genome-edited human cancer models can causally link multiple mutations to phenotype.
• These models provide a platform for studying genotype-phenotype relationships in melanoma.
• Understanding these relationships is crucial for targeted cancer therapies.