Associate Professor, Medicine, Hematology Oncology Division; Feinberg School of Medicine
TRIST-Gastrointestinal Cancers,Tumor Invasion, Metastasis & Angiogenesis
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Pancreatic ductal adenocarcinoma is currently the fourth leading cause of cancer-related death in the US, with a median survival time after diagnosis of less than 6 months and a 5-year disease-free survival of less than 5%. Pancreatic cancer is commonly associated with pronounced collagen-rich fibrotic reaction. We have found that there is significant cross-talk between type I collagen and the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in regulating pancreatic cancer invasion. MT1-MMP is overexpressed in human pancreatic tumors particularly in areas of pronounced fibrosis. To better understand the role of MT1-MMP in vivo, we have created transgenic mice that can be targeted to express MT1-MMP in the pancreas, and have crossed these mice with mice expressing mutant KrasG12D. Excitingly, co-expression of human MMP-14 and K-rasG12D in the pancreas results in large, cystic, papillary lesions consistent with human intraductal papillary mucinous neoplasms. Surprisingly, these lesions have very pronounced fibrotic reaction and are associated with increased TGF-? signaling and activation of stellate cells.
We have also been examining whether the interplay between collagen and MT1-MMP is involved in resistance of pancreatic cancer cells to gemcitabine chemotherapy. Recent reports have suggested that the fibrotic reaction limits the delivery and effectiveness of current therapies in pancreatic cancer. Consequently, my research group has been examining the extent to which type I collagen contributes to gemcitabine resistance. We have found that cells grown in 3D type I collagen are less likely to respond to gemcitabine compared to cells grown atop 3D collagen or on tissue culture plastic. Significantly, we have found that the effect is mediated in part via MT1-MMP. We are currently in the process of characterizing the detailed signaling pathways downstream of MT1-MMP that are involved in chemotherapy resistance in the 3D microenvironment.
We are also interested in understanding how the collagen-rich tumor microenvironment affects expression of the Snail family of transcription factors. We have found that collagen increases expression of Snail via increased TGF-? signaling. We have gone on to show that collagen-induction of Snail is not through the ERK1/2 signaling pathway but involves Smad signaling, in particular Smad3. We have found that expression of Snail increases MT1-MMP expression and causes increased invasion of pancreatic cancer cells, and that human pancreatic tumors with increased Snail levels also have increased MT1-MMP. We are in the process of examining the role of Snail in our mouse models of pancreatic cancer and determining the contribution of Snail to chemotherapy resistance in the 3D microenvironment