MUC1 Regulates TGF-Β Function in Pancreatic Cancer


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Priyanka Grover1,Mahboubeh Yazdanifar1,Mohammad Ahmad1,Ru Zhou1,Angat Puri1,Kajal Grover2,Xinghua Shi1,Pinku Mukherjee1
1University of North Carolina at Charlotte,2University of North Carolina at Chapel Hill

Abstract

Background

Pancreatic Cancer (PC) is the third leading cause of cancer-related deaths in the US. 90% of PC is Pancreatic Ductal Adenocarcinoma (PDA). 80% of PDA overexpress tumor associated Mucin-1 (tMUC1), a membrane bound glycoprotein that is hypo-glycosylated. tMUC1 in PDA plays a critical role in tumor progression and metastasis. Transforming growth factor-β (TGF-β) is a cytokine with dual functionality. Within normal cells and early carcinogenesis, TGF-β functions as a tumor suppressor. This effect is mediated by activation of the SMAD pathway via TGF-β Receptor 1 (TGF-βRI).  However, during later cancer stages, TGF-β becomes a tumor promoter and stimulates migration and invasion thus enhancing metastasis.  This is thought to be mediated by the Erk1/2 pathway via TGF-β Receptor 2 (TGF-βRII). We believe tMUC1 and TGF-β molecular pathways are interconnected. 

Method

TGF-β1 secretion and effects of TGF-β1 to induce apoptosis versus invasiveness in tMUC1 high and low PDA cell lines were determined. Tissue specific gene expression dataset for pancreas 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). Activation of signaling pathways in the presence of TGF-β1 were confirmed in PDA cell lines. Finally, we determined the anti-tumor efficacy of neutralizing TGF-β1 in-vivo in high and low tMUC1-expressing PDA tumors and completed RT-PCR on the tumors.

Results

In response to TGF-β treatment, tMUC1 high PDA cells activated the Erk pathway, while tMUC1 low cells activated the SMAD pathway. The signaling was dependent on MUC1 cytoplasmic tail domain via Src. RNAseq analysis revealed eight genes that showed significant correlation (adjusted p-value<0.05). 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.

Conclusion

tMUC1 plays a key role in regulating TGF-β’s dual function.