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The cell-intrinsic and cell-extrinsic regulation of oncogenic competence in melanoma Melanoma is a cancer that arises from cells belonging to the melanocytic lineage. Because of its high metastatic potential, melanoma is known to be the most aggressive skin tumor.

The importance of the pre-existing transcriptional landscape: DNA mutations are layered onto existing transcriptional programs of the cell that acquires those alterations. The importance of the pre-existing cellular lineage programs is highlighted by the fact that certain DNA mutations are tumorigenic only in particular cellular contexts, a phenomenon called oncogenic competence. Thanks to the human pluripotent stem cell (hPSC)-based technologies, we can study how oncogenic competence changes at different maturation states along a specific cellular lineage.

In melanoma, we have shown that human progenitor cells are more “competent” to acquire a malignant state compared to mature melanocytes. However, competence can be acquired, and mature melanocytes give rise to melanoma upon expression of ATAD2, an epigenetic factor expressed in human progenitor cells and frequently amplified and overexpressed in melanoma patients.

How oncogenic competence is regulated: Both lineage programs (cell fate) and maturation programs (cell state) regulate oncogenic competence. Those are not only cell-intrinsic processes, as they are also extensively regulated by the cell-extrinsic factors from the microenvironment.

Thanks to the hPSC-based technologies, organoid models and mouse models, we study how oncogenic competence is regulated at the cell-intrinsic level and depending on the microenvironment.