YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution

Farhoud Faraji (), Sydney I. Ramirez, Lauren M. Clubb, Kuniaki Sato, Valeria Burghi, Thomas S. Hoang, Adam Officer, Paola Y. Anguiano Quiroz, William M. G. Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B. Jones, Yuwei Cao, Alfredo A. Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A. Califano, Quinton Smith, Alon Goren, Ophir D. Klein, Pablo Tamayo and J. Silvio Gutkind ()
Additional contact information
Farhoud Faraji: University of California San Diego Health
Sydney I. Ramirez: University of California San Diego Health
Lauren M. Clubb: Biomedical Sciences Graduate Program
Kuniaki Sato: University of California San Diego Health
Valeria Burghi: School of Medicine
Thomas S. Hoang: Biomedical Sciences Graduate Program
Adam Officer: Bioinformatics and Systems Biology Graduate Program
Paola Y. Anguiano Quiroz: University of California San Diego Health
William M. G. Galloway: University of California Irvine
Zbigniew Mikulski: La Jolla Institute for Immunology
Kate Medetgul-Ernar: University of California San Diego Health
Pauline Marangoni: University of California San Francisco
Kyle B. Jones: University of California San Francisco
Yuwei Cao: Biomedical Sciences Graduate Program
Alfredo A. Molinolo: University of California San Diego Health
Kenneth Kim: La Jolla Institute for Immunology
Kanako Sakaguchi: IDEXX Laboratories KK
Joseph A. Califano: University of California San Diego Health
Quinton Smith: University of California Irvine
Alon Goren: University of California San Diego
Ophir D. Klein: University of California San Francisco
Pablo Tamayo: University of California San Diego Health
J. Silvio Gutkind: University of California San Diego Health

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

Date: 2025
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DOI: 10.1038/s41467-024-55660-6

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