c-FOS drives reversible basal to squamous cell carcinoma transition

While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies activator protein 1 (AP-1) family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP-1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible model systems that c-FOS-mediated BST demonstrates reversibility. Blocking EGFR pathway activation after c-FOS induction partially reverts BST in vitro and prevents BST features 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.

Automated summary

The study reveals the dynamic process of transition from basal cell carcinoma to squamous cell carcinoma, identifying the crucial role of AP-1 family members and c-FOS in regulating tumor plasticity. It demonstrates the reversibility of c-FOS-mediated transition and shows that blocking EGFR pathway activation can partially reverse the process. The findings suggest a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance.