YAP-Driven Malignant Reprogramming of Epithelial Stem Cells at Single Cell Resolution
Author:
Gutkind J. Silvio1ORCID, Faraji Farhoud2, Ramirez Sydney3, Clubb Lauren4, Sato Kuniaki4, Quiroz Paola Anguiano4, Galloway William5, Mikulski Zbigniew3, Hoang Thomas4, Medetgul-Ernar Kate4, Marangoni Pauline6, Jones Kyle7, Officer Adam4, Molinolo Alfredo4, Kim Kenneth3, Sakaguchi Kanako8, Califano Joseph9, Smith Quinton5, Klein Ophir10, Tamayo Pablo1
Affiliation:
1. University of California, San Diego 2. University of California San Diego Health Department of Otolaryngology-Head and Neck Surgery and Moores Cancer Center 3. La Jolla Institute of Immunology 4. University of California San Diego Health Moores Cancer Center 5. University of California Irvine Department of Chemical and Biomolecular Engineering 6. Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco 7. University of California San Francisco (UCSF) 8. IDEXX Laboratories KK 9. University of California San Diego 10. Cedars-Sinai Medical Center, Los Angeles
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 cell tracing approaches with spatiotemporally controlled oncogene activation and tumor suppressor inhibition to unveil the processes underlying oral epithelial progenitor cell reprogramming into cancer stem cells (CSCs) at single cell resolution. This revealed the rapid emergence of a distinct stem-like cell state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. Interestingly, CSCs harbor limited cell autonomous invasive capacity, but instead recruit myeloid cells to remodel the basement membrane and ultimately initiate tumor invasion. CSC transcriptional programs are conserved in human carcinomas and associated with poor patient survival. These findings illuminate the process of cancer initiation at single cell resolution, thus identifying candidate targets for early cancer detection and prevention.
Publisher
Research Square Platform LLC
Reference70 articles.
1. 1. Clayton, E., Doupé, D.P., Klein, A.M., Winton, D.J., Simons, B.D., and Jones, P.H. (2007). A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189. 10.1038/nature05574. 2. 2. Sánchez-Danés, A., and Blanpain, C. (2018). Deciphering the cells of origin of squamous cell carcinomas. Nat Rev Cancer 18, 549–561. 10.1038/s41568-018-0024-5. 3. 3. Barker, N., Ridgway, R.A., van Es, J.H., van de Wetering, M., Begthel, H., van den Born, M., Danenberg, E., Clarke, A.R., Sansom, O.J., and Clevers, H. (2009). Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611. 10.1038/nature07602. 4. 4. Ying, Z., Sandoval, M., and Beronja, S. (2018). Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth. Nat Cell Biol 20, 1256–1266. 10.1038/s41556-018-0218-9. 5. 5. Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V.F., Kolettas, E., Niforou, K., Zoumpourlis, V.C., et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637. 10.1038/nature05268.
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