Journal Article

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

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

2025

Overview

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. The molecular mechanisms underlying tumour initiation remain elusive. Here, the authors use spatiotemporally controlled oncogene activation and tumour suppressor inhibition with multi-omics to unveil the role of YAP-mediated oral epithelial progenitor cell reprogramming into tumour-initiating cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/21 / 14/19 / 38/35 / 38/39 / 38/91 / 631/67/1536/1665 / 631/67/70 / 631/80/86/2368 / 64/60 / 82/51 / 96/1 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / Cancer / Carcinogenesis - genetics / Carcinogenesis - pathology / Cell activation / Cell Differentiation / Cell fate / Cell survival / Cellular Reprogramming - genetics / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelial-Mesenchymal Transition - genetics / Gene Expression Regulation, Neoplastic / Head & neck cancer / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / Humanities and Social Sciences / Humans / Hypoxia / Invasiveness / Metastases / Mice / Molecular modelling / multidisciplinary / Myeloid cells / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Oncogenes / Progenitor cells / Science / Science (multidisciplinary) / Signal Transduction / Single-Cell Analysis / Stem cells / Stem Cells - metabolism / Target detection / TOR protein / TOR Serine-Threonine Kinases - metabolism / Transcription activation / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription initiation / Tumor suppressor genes / Tumorigenesis / Tumors / YAP-Signaling Proteins - metabolism / Yes-associated protein