While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its’ underlying mechanism remain poorly understood. Here, using surface markers of resistant skin basal cell carcinomas (BCC-RM) and patient single cell and bulk transcriptomic data, we uncover the dynamic epigenetic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies AP1 family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible in vitro and in vivo model systems that c-FOS-mediated BST remains a reversible process. Preventing the activation of the EGFR pathway after c-FOS induction reverts BST in both mouse models and human tumors. Thus, by identifying the molecular basis of BST, our work reveals a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance.

ESDR249 - C-FOS drives reversible basal to squamous cell carcinoma transition

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING