Abstract 321: MUC1 regulates TGFβ function in pancreatic cancer
Authors: Priyanka Grover, Monica D. Nye, Mahboubeh Yazdanifar, Mohammad Ahmad, Ru Zhou, Lopamudra Das Roy, Kajal Grover, Shu-ta Wu, Sritama Nath, Pinku Mukherjee
Journal: Cancer Research (2017)

Abstract In 2016, Pancreatic Cancer (PC) has moved to 3rd leading cause of cancer-related deaths in the USA with 94% dying within 5 years of diagnosis. 90% of PC is Pancreatic Ductal Adenocarcinoma (PDA), of which 80% of PDA overexpress tumor associated Mucin-1 (tMUC1), a membrane bound glycoprotein that is hypoglycosylated. Overexpression of tMUC1 is associated with metastasis and poor prognosis. However the mechanism remains obscure. Transforming growth factor-β (TGF-β) plays a role in poor prognosis. TGF-β is a cytokine with dual functionality. Within normal cells and early carcinogenesis, TGF-β functions as a tumor suppressor and induces apoptosis. This effect is mediated by activation of the canonical Smad pathway via engagement of TGF-β Receptor 1 (TGF-βRI). However during later stages of cancer, TGF-β becomes a tumor promoter and stimulates epithelial to mesenchymal transition, migration, and invasion thus enhancing metastasis. This TGF-β effect is mediated by the noncanonical Erk1/2 pathway. We have recently shown correlation between tMUC1 and TGF-β within an exogenous tMUC1 model of PDA. Therefore, it is hypothesized that the mechanism between the two newly connected pathways exists in PDA tumors with high endogenous tMUC1 levels. We propose that the tyrosine kinases present in the cytoplasmic tail of tMUC1 are intermediary between the two pathways, thus leading to enhanced metastasis. First the secretion levels of TGF-β1 were assessed in a panel of 13 PDA cell lines with variable expression levels of tMUC1 by ELISA. The effects of TGF-β1 to induce apoptosis versus invasiveness on a variety of tMUC1 high and tMUC1 low PDA cell lines were determined. The effects of tMUC1 knockdown were evaluated in tMUC1 high cell lines via siRNA. We studied the role of tyrosine kinases and other protein complexes in mediating the interactions between tMUC1 and TGF-β via proteomics analysis. Finally, we evaluated the anti-tumor efficacy of neutralizing TGF-β1 in vivo in high and low tMUC1-expressing PDA tumors. In tMUC1 high PDA cells, TGF-β1 is secreted less when compared to tMUC1 low PDA cells, allowing for the more resistant cells to diminish TGF-β mediated effects endogenously. It is shown that with TGF-β1 treatment, tMUC1 high cells are more invasive, resist apoptosis, and activate Erk pathway, while tMUC1 low cells activate SMAD pathway. However, tMUC1 knockdown via siRNA does not affect TGF-β receptor levels. When studying the tyrosine kinases, c-Src becomes more phosphorylated in the presence of TGF-β1 in tMUC1 high cells, while in tMUC1 low cells c-Src becomes more deactivated in the presence of TGF-β1. Finally, within the mouse model, tMUC1-high PDA tumors respond to the neutralization of TGF-β1 by decreasing tumor size, while having no statistical effect on tMUC1-low PDA tumors. tMUC1 expression is influential in TGF-β function in an endogenous model. Neutralizing TGF-β in tMUC1 high expressing tumors can be considered as a possible treatment. This has high clinical significance for patients with PDA. Citation Format: Priyanka Grover, Monica D. Nye, Mahboubeh Yazdanifar, Mohammad Ahmad, Ru Zhou, Lopamudra Das Roy, Kajal Grover, Shu-ta Wu, Sritama Nath, Pinku Mukherjee. MUC1 regulates TGFβ function in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 321. doi:10.1158/1538-7445.AM2017-321