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.
|LeBleu, Valerie S; O'Connell, Joyce T; Gonzalez Herrera, Karina N et al. (2014) PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992-1003, 1-15|
|Melo, Sonia A; Sugimoto, Hikaru; O'Connell, Joyce T et al. (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707-21|
|Charytan, David M; Padera, Robert; Helfand, Alexander M et al. (2014) Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease. Int J Cardiol 176:99-109|
|Özdemir, 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|
|Rubashkin, Matthew G; Ou, Guanqing; Weaver, Valerie M (2014) Deconstructing signaling in three dimensions. Biochemistry 53:2078-90|
|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|
|Rahman, Mohummad Aminur; Kristiansen, Per E; Veiseth, Silje V et al. (2014) The arabidopsis histone methyltransferase SUVR4 binds ubiquitin via a domain with a four-helix bundle structure. Biochemistry 53:2091-100|
|Tampe, Björn; Tampe, Desiree; Müller, Claudia A et al. (2014) Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol 25:905-12|
|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|
|Kahlert, Christoph; Melo, Sonia A; Protopopov, Alexei et al. (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869-75|
Showing the most recent 10 out of 22 publications