c-FOS drives reversible basal to squamous cell carcinoma transition
François Kuonen,
Nancy Yanzhe Li,
Daniel Haensel,
Tiffany Patel,
Sadhana Gaddam,
Laura Yerly,
Kerri Rieger,
Sumaira Aasi,
Anthony E. Oro
Affiliations
François Kuonen
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA; Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, 1011 Lausanne, Switzerland; Corresponding author
Nancy Yanzhe Li
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Daniel Haensel
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Tiffany Patel
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Sadhana Gaddam
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Laura Yerly
Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, 1011 Lausanne, Switzerland
Kerri Rieger
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Sumaira Aasi
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
Anthony E. Oro
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA; Corresponding author
Summary: 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.
