A NOVEL ROLE FOR SMAD6 IN THE BIOLOGY OF PANCREATIC CANCER
Brosnan-Cashman, Jacqueline Ann
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Pancreatic cancer is a nearly uniformly lethal disease, with the five-year survival rate remaining a dismal five percent. Recently, our laboratory has associated the loss of SMAD4, a critical mediator of TGF-β and BMP signaling, with the presence of widely disseminated pancreatic cancer. Therefore, we sought to obtain a better understanding of these pathways in the biology of pancreatic cancer through analysis of SMAD4 loss and SMAD6 elevation. To gain a better understanding of the role of SMAD4 loss in pancreatic cancer, we established isogenic cell lines from pancreatic cancer cells that were SMAD4-deficient, such that these cell lines were SMAD4-complemented. We were able to show that restoration of SMAD4 into these cell lines hindered their ability to proliferate, migrate, and invade through matrigel in vitro. Furthermore, we sought to gain an understanding of the utility of SMAD4 as a marker for the efficacy of chemotherapy. We have shown that SMAD4 status is predictive of a small, but statistically significant, in vitro response to cisplatin and irinotecan and resistance to gemcitabine. Second, we identified SMAD6, previously described as an inhibitor of both TGF-β and BMP, as being differentially expressed in pancreatic cancer cell lines and tissues. SMAD6 expression was found not to be regulated by genetic mutation or degree of RNA transcription, but through aberrant proteolytic degradation. It is through loss of this regulatory mechanism that SMAD6 expression becomes elevated, leading to increased levels of proliferation, migration, and invasion through matrigel, in vitro, and increased metastatic burden in patients. Despite its previously described role as an inhibitor of TGF-β and BMP signaling, we have determined that the effects of SMAD6 on pancreatic cancer cells are independent of this function. Rather, we have identified a nuclear role for SMAD6: SMAD6 is able to bind to DNA in pancreatic cancer, and is constitutively located in the nucleus of pancreatic cancer cells. Therefore, both SMAD4 loss and SMAD6 overexpression negatively impact the biology of pancreatic cancer, albeit through different mechanisms. Further study will continue to elucidate the role of these proteins in the biology of pancreatic cancer.