Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151925-03
Application #
8318838
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mohla, Suresh
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Pickup, Michael W; Owens, Philip; Gorska, Agnieszka E et al. (2017) Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells. Cancer Immunol Res 5:718-729
Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W et al. (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22:497-505
Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-497
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
Lovisa, Sara; LeBleu, Valerie S; Tampe, Björn 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 527:525-530
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
Ou, Guanqing; Weaver, Valerie Marie (2015) Tumor-induced solid stress activates ?-catenin signaling to drive malignant behavior in normal, tumor-adjacent cells. Bioessays 37:1293-7
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
Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie et al. (2014) Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol 184:2687-98

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