Abstract 3464: MUC1 regulates TGF-β in pancreatic cancer

Abstract

Abstract Pancreatic Cancer (PC) is the 3rd leading cause of cancer-related deaths in the US. 90% of PC is Pancreatic Ductal Adenocarcinoma (PDA). 85% of PDA overexpress tumor associated Mucin-1 (tMUC1), a membrane bound glycoprotein that is aberrantly glycosylated. tMUC1 overexpression in PDA plays a critical role in tumor progression and metastasis, however, the mechanism remains elusive. Transforming growth factor-β (TGF-β) is a cytokine with a 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 the TGF-β Receptor 1 (TGF-βRI). However, during later stages of cancer, TGF-β becomes a tumor promoter and stimulates EMT, migration, and invasion. This effect is thought to be mediated by the non-canonical Erk1/2 pathway. We have recently shown that high tMUC1-expressing PDA cells respond to TGF-β via activation of the non-canonical pathway and undergoes EMT whereas, low tMUC1 expressing PDA cells respond to TGF-β via activation of the canonical SMAD pathway and undergoes apoptosis. Hypothesis: tMUC1 and TGF-β molecular pathways are interconnected and that tMUC1 plays a key role in regulating TGF-β's dual function. Method: The effects of TGF-β1 to induce apoptosis versus invasiveness in a variety of tMUC1 high and low PDA cell lines were determined. Tissue specific gene expression dataset from healthy subjects were collected from the GTEx Project (n=171). Tumor-specific gene expression data from PDA patients were collected from the TCGA-PAAD project (n=178). The Pearson's correlation coefficient was calculated for TGF-β1 canonical and non-canonical pathway genes and MUC1 and the p-values adjusted using Bonferroni multiple-testing correction. Finally, we determined the anti-tumor efficacy of neutralizing TGF-β1 in vivo in high and low tMUC1-expressing PDA tumors. Results: In response to TGF-β treatment, tMUC1 high PDA cells resisted apoptosis, enhanced their invasiveness, and activated the Erk pathway, while tMUC1 low cells became apoptotic and activated the SMAD pathway. The signaling was dependent upon tyrosine phosphorylation of MUC1 cytoplasmic tail domain by Src. RNA-Seq analysis in human populations reveal eight genes that show significant correlation (low p-value OR p-value < 0.05) in the TCGA PDA tissue which were insignificant in the GTEx healthy tissue. A moderate positive correlation was identified for MAPK3/ERK1(r= 0.549, corrected p-value = 4.47x10^-14) and SRC (r=0.592, corrected p-value = 6.3x10^-17). In contrast, a moderate negative correlation coefficients were identified for PLCG1 (r=-0.406, corrected p-value =3.86x10^-07), SMAD2(r=-0.38, corrected p-value=3.38x10^-06), and TGFβ3 (r=-0.32, corrected p-value =2.3x10^-06). Finally, in mice, tMUC1-high PDA tumors responded to the neutralization of TGF-β1 by significantly reducing tumor growth, while having no effect on tMUC1-low PDA tumors. Citation Format: Priyanka Grover, Mahboubeh Yazdanifar, Mohammad Ahmad, Ru Zhou, Angat Puri, Kajal Grover, Xinghua Shi, Pinku Mukherjee. MUC1 regulates TGF-β in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3464.