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[Preprint]. 2024 Oct 21:2023.07.24.550427. Originally published 2023 Jul 26. [Version 2] doi: 10.1101/2023.07.24.550427

YAP-Driven Oral Epithelial Stem Cell Malignant Reprogramming at Single Cell Resolution

Farhoud Faraji, Sydney I Ramirez, Lauren Clubb, Kuniaki Sato, Valeria Burghi, Thomas S Hoang, Adam Officer, Paola Y Anguiano Quiroz, William MG Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B Jones, Alfredo A Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A Califano, Quinton Smith, Alon Goren, Ophir D Klein, Pablo Tamayo, J Silvio Gutkind
PMCID: PMC10402053  PMID: 37546810

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 (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC 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.

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