Figure 3. Melanoma-derived iPSC to model cell of origin and drug resistance.

(A) Melanocytes populate multiple locations as their diverse developmental origins from NCC Melanomas emerge from multiple locations of melanocytes. Reprogramming skin-derived fibroblasts and melanocytes into iPSC and differentiation into melanocytes results in efficient iPSC reprogramming and melanocyte differentiation. However, melanoma cells reprogrammed to iPSC and directed to differentiate back to melanocytes do not exhibit melanocyte differentiation but neural/NCC-like mixed phenotype. Melanoma iPSC-differentiated cells show increased expression of neural/NCC and melanoma stem cell-related markers and decreased expression of melanocytic lineage markers. (B) During malignant transformation, melanocytes acquire BRAFV600E oncogenic mutation and other mutations such as PTEN loss. These cells are initially sensitive to vemurafenib, but after treatment with the inhibitor, the drug induces changes in expression related to cellular plastic changes generating a stem cell-like transitional state. After this transition, many cells survive, have made plastic changes with stem-like characteristics, and exhibit acquired resistance to the drug (top). Reprogramming of BRAFV600E melanoma cells induces the formation of iPSC colonies. iPSC generated do not differentiate into melanocytes but exhibit neural/NCC-like plasticity and show acquired resistance (bottom).