This U01 proposal is designed to be part of the network for the study of tumor microenvironment (TMEN) and seeks to improve our understanding of the critical steps involved the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) to a level that will permit the rational development of effective stromal specific therapeutic agents. Pancreatic cancer is the fourth leading cause of cancer death in the US. In 2004, 31,270 deaths were recorded. This disease is devastating and currently specific therapies are lacking and it leads to rapid death of all patients, coupled with pain and despair. The economic toll of pancreatic cancer is estimated at about $3.7 billion dollars to the US healthcare system. The central focus of this project is to elucidate the molecular mechanisms by which fibroblasts/mesenchymal cells, myeloid/immune cells (MIC) and extracellular matrix (ECM) may contribute to the origin and progression of PDAC. While, invasive PDAC is significantly associated with a marked desmoplastic reaction (one of highest of all human tumors), significant recruitment of fibroblasts/myofibroblasts and ensuing fibrosis, the functional contribution of stromal fibroblasts in PDAC pathogenesis is not known. This application tests the central hypothesis that "stromal fibroblasts are rate limiting determinants of PDAC progression". The new mouse models described in this project will provide a basic knowledge regarding the role of stromal fibroblasts, immune cells and ECM biochemistry in PDAC and explore potential PDAC microenvironment specific therapeutic opportunities. The proposal brings together the laboratories of Drs. Kalluri, Moses and Weaver, with complementary expertise to the study PDAC microenvironment. The proposal is divided into three specific aims.
Specific Aim 1 : Determine the functional contribution of stromal fibroblasts in the pathogenesis of PDAC.
Specific aim 2. Determine the role of chemokines and host myeloid/immune cells (MICs) in the pathogenesis of PDAC.
Specific Aim 3. Determine whether increased tissue tension drives pancreatic adenocarcinoma aggression.
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|Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-97|
|Northcott, Josette M; Northey, Jason J; Barnes, J Matthew et al. (2015) Fighting the force: Potential of homeobox genes for tumor microenvironment regulation. Biochim Biophys Acta 1855:248-53|
|Lovisa, Sara; LeBleu, Valerie S; Tampe, BjÃ¶rn et al. (2015) Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21:998-1009|
|Zheng, Xiaofeng; Carstens, Julienne L; Kim, Jiha et al. (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525-30|
|Melo, Sonia A; Luecke, Linda B; Kahlert, Christoph et al. (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:177-82|
|Keskin, Doruk; Kim, Jiha; Cooke, Vesselina G et al. (2015) Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep 10:1066-81|
|Ou, Guanqing; Weaver, Valerie Marie (2015) Tumor-induced solid stress activates Î²-catenin signaling to drive malignant behavior in normal, tumor-adjacent cells. Bioessays 37:1293-7|
|Ã–zdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L et al. (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719-34|
|Carstens, Julienne L; Lovisa, Sara; Kalluri, Raghu (2014) Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch. J Clin Invest 124:1458-60|
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