MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition

Abstract

Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this process by repressing E-cadherin and enhancing vimentin and N-Cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT which translates to increased invasiveness and metastasis. EMT was significantly reduced when Muc1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR, and Western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared to cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.

Tissue mechanics regulate brain development, homeostasis and disease

“…Mesenchymal GBM cells, which resemble migratory cells of the neural crest, are associated with increased treatment resistance, and when GBM recurs after standard-of-care therapy, mesenchymal cells are observed at a higher frequency (Lu et al, 2012). Cells which have undergone EMT often present with an altered glycocalyx, the saccharide-protein network on the cell surface (Roy et al, 2011;Porsch et al, 2013;Moustakas and Heldin, 2014). A strong glycocalyx elicits pro-tumorigenic effects by enhancing focal adhesion formation and downstream signaling (Paszek et al, 2014), and has also been implicated in resistance to small-molecule and antibody therapies because it provides a physical shield to the cell membrane and its associated receptors (Yang et al, 2013;Thompson et al, 2010;Singha et al, 2015).…”

Molecular alterations that drive breast cancer metastasis to bone

“…In addition, MUC1 in MUC CT mice did not immunoprecipitate with or cause nuclear translocation of b-catenin, thereby blocking the transcription of genes associated with EMT. 39 Studies utilising models of triple-negative breast cancer have shown that MUC4 mucin enhances the invasive and migratory potential of cancer cells through upregulation of EGFR family proteins. A separate study demonstrated that knockdown of MUC4 in breast cancer cells leads to molecular and biochemical alterations that are necessary for EMT, including reduced expression of mesenchymal markers such as vimentin and vitronectin and increased expression of the epithelial marker cytokeratin 18.…”

Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity inC. elegans

“…For example, in the Drosophila trachea, a temporary chitinous apical ECM controls tube length (Devine et al, 2005;Tonning et al, 2005) and the ZP-domain proteins Piopio and Dumpy influence junction remodeling (Jazwinska et al, 2003). In humans, overexpression of the mucin MUC1 is observed in >90% of metastatic pancreatic ductal adenocarcinoma, and MUC1 can influence EMT in mouse models (Kufe, 2009;Roy et al, 2011). However, we still have a limited understanding of how the apical ECM contributes to epithelial morphology and junction dynamics.…”