Pancreatic cancer is a devastating disease with dismal median survival of 3-6 months. The disease is characterized by highly aggressive tumors that are resistant to standard chemo and radiation therapies. MUC1 is a transmembrane mucin glycoprotein that is significantly increased and differentially glycosylated in over 60% of human pancreatic adenocarcinomas (PDA). Further, MUC1 is a marker of aggressive PDA, as its expression is correlated with high metastases, drug resistance, and poor prognosis. However, the underlying mechanisms of MUC1 associated aggressiveness remain unclear. We have new preliminary evidence that PDA cells that do not express MUC1 undergo apoptosis in response to TGF-? whereas PDA cells that express MUC1 undergo EMT and invasion in response to TGF-?. The TGF-?-induced invasion is completely lost when the cytoplasmic tail of MUC1 (MUC1 CT) is mutated. Therefore signal transduction through MUC1 CT is necessary for TGF-?-induced invasion to occur. TGF-? is a major player in carcinogenesis, and is well known for its paradoxical role as both a tumor suppressor and a tumor promoter in pancreatic cancer. Understanding the factors and signals that drive TGF-? function to switch from tumor-suppressor to tumor-promoter is of great interest. We hypothesize that signaling through MUC1-CT supports TGF-?-induced EMT and invasion and inhibits TGF-?-induced apoptosis.
The specific aims are: 1) to determine the differential effects of TGF-? induced EMT in MUC1+, MUC1-, and MUC1+ cells in which the tyrosine residues in the MUC1 CT have been mutated to phenylalanine (MUC1 Y0);2) to determine the differential effects of TGF-? induced apoptosis in MUC1+, MUC1-, and MUC1 Y0 cells. Both in vitro and in vivo experiments are proposed for the aims. If the hypothesis is true, this will be the first demonstration that MUC1 acts as a switch in PDA cells, changing the pro-apoptotic property of TGF-? to an anti-apoptotic and pro-survival property. The knowledge gained will have to be considered when developing future therapies that aim to target the tumor promoting signals of TGF-? while still retaining the pro-apoptotic signals of TGF-?. So far, MUC1 therapeutics has focused on the extracellular region of MUC1 which has not led to clinical success. If the hypothesis holds true, then developing drugs that specifically target MUC1 CT signaling should become a priority.
Based on new preliminary data, we hypothesize that MUC1;a tumor associated glycoprotein can influence the functional properties of a major multifaceted growth factor, TGF-? in pancreatic cancer. We propose to demonstrate that MUC1 acts as a switch in pancreatic cancer cells, changing the cellular response to TGF-? from tumor suppressor to tumor promoter. Thus future therapies may aim to target the tumor promoting signals of TGF-? in some patients while still retaining the tumor suppressive property of TGF-? in others.
|Nath, Sritama; Mukherjee, Pinku (2014) MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med 20:332-42|