(202b) Time and Length Scales for Hypoxia-Mediated Cell Signaling in Pancreas Cancer

A memorable problem from Bill’s Analysis of Transport Phenomena textbook models the dynamically determined length scale over which oxygen is depleted in poorly vascularized tissues. The physical effects described in that problem can be visualized in solid tumors using reagents such as pimonidazole followed by immunohistochemistry, and the results of such experiments demonstrate that substantial intratumoral heterogeneity may exist with respect to oxygen tension. While it is well known that hypoxia can trigger the secretion of angiogenic factors, tumor cell responses to low oxygen tension can be substantially more complex than this isolated effect and may involve broad transcriptional, signaling, and epigenetic rewiring. My lab has proposed that the hypoxic tumor microenvironment in pancreas cancer activates multiple kinase-regulated signaling pathways that cooperate to drive epithelial-mesenchymal transition (EMT), a normal cellular developmental program that occurs aberrantly in various carcinomas to promote chemoresistance and metastasis. If validated, this conceptual model may provide one explanation for the EMT heterogeneity typically observed among cells in pancreas cancer – i.e., spatial heterogeneity in oxygen tension due to limitations in oxygen transport may drive heterogeneity in the EMT phenotype. In this presentation, I will describe our experimental efforts to identify the hypoxia-mediated cell signaling processes that regulate EMT in pancreas cancer and the time scales over which they operate. I will also describe our use of data science models to establish a connection between hypoxia and EMT. This cancer biology problem naturally integrates considerations of transport and cell signaling over multiple time and length scales in the tumor microenvironment, and the results have implications for the design of combination therapy for pancreas cancer.