Metabolic interactions in the pancreatic tumor microenvironment

点击翻译按钮获取中文摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a deadly form of cancer with few treatment options available to patients. Modern advances in chemotherapy and immunotherapy have yet to provide effective treatments. While oncogenic mutations in Kras are nearly universal in PDA, to date Kras remains undruggable. Clearly, new strategies are needed to develop more effective strategies to improve outcomes in PDA. The metabolic pathways utilized by PDA cells present attractive targets to exploit therapeutically. The cells in a pancreatic tumor are nutrient-deprived and persist in a hypoxic environment. High intratumoral pressure caused by excessive extracellular matrix deposition from the cancer-associated fibroblasts (CAFs) prevents proper vascularization, nutrient delivery, and waste removal. Predictably, PDA cells hijack normal metabolic pathways to meet the biosynthetic and energetic demands required to survive and proliferate. In addition, cancer cells also utilize non-cell autonomous pathways to meet metabolic demands. Thus, strategies targeting tumor metabolism must also take into consideration the role of the diverse cell types in the tumor microenvironment. Previous work in my lab revealed that PDA cells utilize glutamate oxaloacetate transaminase 2 (GOT2) to protect against stress and support proliferation. Despite this profound growth inhibitory effect in vitro, I found that GOT2 knockdown (KD) PDA tumors were able to grow in vivo. My preliminary data indicate that culturing PDA GOT2KD cells in media conditioned by cancer-associated fibroblasts (CAFs), which are highly prevalent in an in vivo pancreatic tumor, restores proliferation in vitro. I then identified pyruvate as the single factor in CAF media that restored growth upon GOT2 knockdown and protected PDA cells from mitochondrial inhibitors. The working hypothesis of this proposal is that CAFs support PDA metabolism when redox homeostasis and mitochondrial respiration are disrupted. This hypothesis will be tested in two aims. In Aim 1, I will seek to discover how CAFs are producing and releasing pyruvate. Aim 2 will elucidate the mechanism by which pyruvate supports PDA growth during mitochondrial inhibition. Further, I will test the role of this pathway in PDA tumor growth using preclinical mouse models of pancreatic cancer to determine the therapeutic utility of targeting mitochondrial metabolism and pyruvate-releasing CAFs in PDA.