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YAP-Driven Malignant Reprogramming of Epithelial Stem Cells at Single Cell Resolution.

Jorge Silvio GutkindFarhoud FarajiSydney RamirezLauren ClubbKuniaki SatoPaola Anguiano QuirozWilliam GallowayZbigniew MikulskiThomas HoangKate Medetgul-ErnarPauline MarangoniKyle JonesAdam OfficerAlfredo MolinoloKenneth KimKanako SakaguchiJoseph CalifanoQuinton SmithOphir KleinPablo Tamayo
Published in: Research square (2023)
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.
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