Overall - Abstract/Summary. This multi-disciplinary team focuses on the role of oncogenic Kras (Kras*) in pancreatic ductal adenocarcinoma (PDAC) with an emphasis on understanding the interplay between Kras* cancer cells and the tumor microenvironment (TME). Our objectives are to elucidate cancer cell intrinsic and TME mechanisms responsible for resistance to Kras* extinction as well as to define co-dependent circuits controlling metabolism and immunity. Our P01 program comprises three highly interdependent projects and three essential scientific cores. Project 1 (DePinho with Allison) will continue to focus on elucidating the functional basis for escape from Kras* dependence, which includes intrinsic mechanisms as well as paracrine signaling involving myeloid populations. These cancer cell-TME interactions also uncovered the importance of myeloid cells in suppressing tumor immunity, providing the basis for rational development of novel immunotherapy regimens with truly unprecedented anti-tumor responses. Project 2 (Bardeesy with Kimmelman and Cantley) has studied the role of Kras* in driving anabolic growth of cancer cells and the importance of lysosomal degradative pathways in both tumor cell metabolic homeostasis and immune evasion, leading to new clinical trials testing autophagy inhibition in PDAC. Project 2 now seeks to explore how specific oncogenes/tumor suppressors co-mutated with Kras* influence metabolic dependencies as well as the immune composition of the TME. Project 3 (Kalluri with Ying) brings together these two concepts of immunity and metabolism in the context of the unique stromal biology of PDAC. Specifically, tumor immunity and metabolism are explored from the viewpoint of a novel Kras*-induced paracrine program involving a unique oncogenic type I collagen variant and a3b1 integrin signaling in the TME. Project 3 also utilizes its exosome technology platform in targeting Kras* combined with refined immune or metabolism regimens emerging from the other projects. The close interaction of each Projects with various clinical platforms, including the Immunotherapy Platform and the Parker Institute for Cancer Immunotherapy at MD Anderson directed by Dr. James Allison (Investigator of Project 1), will constantly inform the work from this P01 team and, vice versa, guide the clinical trials in real time. Highly innovative Cores for Pathology (Maitra), Modeling & Experimental Therapeutics (Horner), Computation (Futreal), along with the Administrative Core will enable the full potential of these Projects.