Signaling Regulation of the Epithelial-Mesenchymal Transition in the Hypoxic Pancreas Cancer Microenvironment 263 views

The tumor microenvironment contributes to the progression of pancreatic ductal adenocarcinoma (PDAC), an almost uniformly lethal disease. Here, we demonstrate how tumor hypoxia resulting from characteristic PDAC hypovascularity drives epithelial-mesenchymal transition (EMT), a cellular program that occurs early in metastasis and promotes chemoresistance. The work described in this thesis establishes hypoxia as a bona fide driver of EMT in pancreas cancer and uncovers the molecular mechanisms through which hypoxia promotes a heterogeneous, but highly durable, EMT in transformed PDAC ductal cells. Multiple mouse models, publicly available human patient data, single-cell and bulk omics, cell-based assays, and data science models are employed to gain a comprehensive and systematic understanding of the signal transduction and epigenetic regulatory processes governing hypoxia-mediated EMT. We find that neoplastic PDAC cells preferentially undergo EMT in hypoxic tumor regions and that hypoxia drives a cell-autonomous EMT in PDAC cells that is substantially more persistent than EMT in response to growth factors. We further identify an oxygen-dependent histone methylation-MAPK signaling positive feedback process that is responsible for driving EMT in response to hypoxia. The signaling process initiated by low oxygen tension that leads to durable phenotype switching can be pharmacologically targeted to inhibit, and even reverse, hypoxia-mediated EMT. Further, through single-cell RNA-sequencing, we uncover the transcriptional basis for the heterogeneity of hypoxia- and growth factor-mediated EMT. We identify context-dependent transcripts that preferentially control EMT by actively suppressing or promoting the mesenchymal state in hypoxic culture, but not in response to growth factors. Collectively, these findings identify several potential vulnerabilities in hypoxia-mediated signaling for EMT in PDAC and nominate specific targeted inhibitors for incorporation into combination therapies designed to augment chemoresponse by antagonizing EMT.

PHD (Doctor of Philosophy)

Pancreas Cancer; Epithelial-mesenchymal transition; Hypoxia

English

2023-01-31