Cancer cell phenotype plasticity as a driver of immune escape and resistance in melanoma

Cutaneous melanoma is the deadliest form of skin cancer, characterized by an exacerbated cancer cell plasticity that contributes to intra-tumor heterogeneity and resistance to treatment. Despite recent progress provided by targeted and immunotherapy, a significant number of metastatic melanoma patients still present innate or acquired resistance. Increasing evidence indicate that in addition to genetic alterations, resistance development may be attributed to phenotypic adaptations through transcriptional and epigenetic processes. A complete understanding of the reprogramming mechanisms underlying phenotypic adaptations of melanoma cells, their complex interplay with the tumor microenvironment and thus, their exceptional capacity to develop resistance to current therapeutic strategies, is still required in order to define novel targets and design new combination therapies. Our work demonstrated that embryonic transcription factors known for their role in EMT (epithelial-to-mesenchymal transition) in carcinomas, also play major functions in melanoma, that extend beyond metastatic dissemination. Indeed, a melanocyte-lineage specific EMT-TF reprogramming regulates melanomagenesis and melanoma cell plasticity. I will present how ZEB1 regulates phenotype switching from a proliferative/differentiated towards an invasive/stem-like state, resistant to targeted therapies, and contributes to immune escape and resistance by shaping the immune microenvironment.

Email : julie.caramel@lyon.unicancer.fr

Benboubker V et al. Cancer cell phenotype plasticity as a driver of immune escape in melanoma. Frontiers in Immunology, 2022.

Plaschka M, et al. ZEB1 transcription factor promotes immune escape in melanoma. J Immunother Cancer, 2022.

Caramel J, Ligier M, Puisieux A. Pleiotropic roles for ZEB1 in Cancer. Cancer Research, 2018, 78: 30-35.

Richard G, et al. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol Med. 2016. 8: 1143-1161.

Caramel J., et al. A Switch in the Expression of Embryonic EMT-Inducers Drives the Development of Malignant Melanoma. Cancer Cell 2013, 24, 466-480

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