- Project 2 (Role of Lysosomal Scavenging in PDAC Metabolism) Kras mutation (KRAS*) is the signature genetic alteration in pancreatic ductal adenocarcinoma (PDAC) that our P01 team and others have demonstrated to be critical to disease genesis and maintenance. While inhibitors of KRAS* have proven difficult to develop, alterations in cellular metabolism have emerged as promising targets for therapeutic intervention. Indeed, we have discovered that a major function of KRAS* in tumor maintenance is to orchestrate the profound metabolic rewiring of PDAC cells, including alterations in glucose and glutamine utilization. Furthermore, we have broadly elucidated additional metabolic dependencies of KRAS* PDAC. PDAC exhibit a strikingly high level of nutrient scavenging via autophagy and macropinocytosis. These processes converge at the lysosome where cargo (extracellular, from macropinocytosis; intracellular, from autophagy) is degraded and the resulting metabolites are recycled for use in anabolic and bioenergetic pathways. Indeed we and others have shown that these scavenging processes are critical for PDAC growth and metabolic homeostasis. We have also identified a regulatory network responsible for induction and integration of these recycling pathways. Based on these findings, the goals of Project 2 are to: 1) identify the metabolic outputs of these lysosomal pathways and how they integrate with cellular metabolism; 2) decipher the circuits that reprogram PDAC to rely on these pathways; 3) define signatures predicting reliance on these pathways; and 4) identify combinatorial approaches that effectively target this dependency and prevent metabolic escape. Our highly integrated joint studies will explore these processes in cells that escape Kras* inactivation (with Project 1) and in innovative models for tumor-stroma interactions (with Project 3), and depend on the Cores for tissue, drug screening, therapeutics and computational resources. Given ongoing clinical trials with the lysosomal inhibitor, hydroxychloroquine, these studies can have a transformative impact on PDAC treatment. At the same time, the full translational potential of our work requires integrated understanding of synergies/interferences of targeting salvage pathways, metabolic processes, Kras* effectors, Kras* bypass mechanisms and immune cells. The need for this integrated view is a central rationale of the P01 program.
- Project 2 (Role of Lysosomal Scavenging in PDAC Metabolism) Pancreatic ductal adenocarcinomas (PDAC) exhibit a strikingly high level of nutrient scavenging pathways converging on the lysosome that are required for tumor growth. This project aims to decipher the key regulatory pathways controlling nutrient scavenging in PDAC, to identify the critical contributions to lysosome- derived substrates to PDAC metabolism, and to define effective therapies targeting these pathways.
|Lundquist, Mark R; Goncalves, Marcus D; Loughran, Ryan M et al. (2018) Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Mol Cell 70:531-544.e9|
|Hopkins, Benjamin D; Pauli, Chantal; Du, Xing et al. (2018) Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560:499-503|
|Biancur, Douglas E; Kimmelman, Alec C (2018) The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim Biophys Acta Rev Cancer 1870:67-75|
|Chen, Yang; LeBleu, Valerie S; Carstens, Julienne L et al. (2018) Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol Med 10:|
|Hill, Margaret A; Alexander, William B; Guo, Bing et al. (2018) Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma. Cancer Res 78:4445-4451|
|Mendt, Mayela; Kamerkar, Sushrut; Sugimoto, Hikaru et al. (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3:|
|Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822|
|Anglin, Justin; Zavareh, Reza Beheshti; Sander, Philipp N et al. (2018) Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma. Bioorg Med Chem Lett 28:2675-2678|
|Yang, Annan; Herter-Sprie, Grit; Zhang, Haikuo et al. (2018) Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms. Cancer Discov 8:276-287|
|Santana-Codina, Naiara; Roeth, Anjali A; Zhang, Yi et al. (2018) Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat Commun 9:4945|
Showing the most recent 10 out of 134 publications