Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the U. S. The median survival time after diagnosis is less than 6 months, while 5-year disease-free survival is less than 5%. Poor outcome is attributed to the relatively advanced stage of disease at time of diagnosis, with approximately 80% of patients presenting with locally aggressive or metastatic disease. PDAC is associated with an intense fibrotic reaction around the tumor known as desmoplastic reaction. This reaction is composed of interstitial extracellular matrix (ECM), predominantly type I collagen, together with proliferating fibroblastic cells. However, the functional interactions among the pancreatic ductal cells, the interstitial ECM and the stromal fibroblasts are poorly understood. According to the NCI Pancreatic Cancer Progress Review Group 'a better understanding is needed of the basic mechanisms involved in the development of the stroma, its interaction with the pancreatic cancer cells and its role in the pathogenesis of pancreatic cancer'. We have demonstrated that extracellular matrix deposited by pancreatic fibroblasts promotes TGF-?1 expression by PDAC cells followed by increased MT1-MMP expression [Ottaviano AJ et al, Cancer Research 2006]. Our preliminary data also indicate that MT1-MMP increases cyclin D1 expression and enhances p38 MAPK signaling to promote growth in collagen-rich microenvironment. Moreover, our preliminary data suggest that expression of MT1- MMP in the pancreas using a transgenic mouse model increases fibrosis. Together these data support our central hypothesis that a feed-forward amplification loop involving cross-talk between type I collagen, TGF-?1 and MT1-MMP contributes to the aggressive phenotype of PDAC: the desmoplastic reaction promotes TGF-?1 expression and signaling to increase MT1-MMP expression, but this in turn contributes to expanded fibrosis and a further increase in TGF-?1 signaling and MT1-MMP expression, thus enhancing PDAC invasion and metastasis. Experiments proposed in Aim 1 have been designed to understand the first half of the amplification loop (fibrosis ? TGF-?1 ? MT1-MMP) by elucidating the mechanism by which the ECM, in particular type I collagen, increases TGF-?1 and MT1-MMP expression by PDAC cells.
In Aim 2 we will examine the second half of the amplification loop (MT1- MMP ? fibrosis and growth in 3D collagen) by elucidating the mechanism by which MT1-MMP promotes fibrosis and facilitates pancreatic tumor growth in a collagen-rich microenvironment using organotypic, orthotopic and transgenic models of pancreatic cancer. Our rationale for these proposed studies is that once the mechanism of cross-talk between the fibrotic reaction and PDAC cells is fully determined, this information may ultimately lead to new treatment strategies that reduce the morbidity and mortality of pancreatic cancer.
The relatively high mortality resulting from pancreatic ductal adenocarcinoma (PDAC) is largely due to the fact that approximately 80% of patients present with locally invasive or metastatic disease at the time of diagnosis. PDAC is frequently associated with an intense area of collagen-rich fibrosis surrounding the tumor known as the desmoplastic reaction. While the desmoplastic reaction is likely an important precursor to the development of PDAC local invasion, and perhaps metastases as well, the precise mechanisms that contribute to these processes are currently not well understood. The objective of this application is to delineate the molecular mechanisms by which desmoplastic reaction contributes to PDAC progression, and once the mechanism of cross-talk between the fibrotic reaction and PDAC cells is fully determined, we predict that this will lead to new treatment strategies that reduce the morbidity and mortality of pancreatic cancer. ? ? ?
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