Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers.Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumorsuppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK 2 pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibody in vivo showing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β's paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.

Potential of Anti-MUC1 Antibodies as a Targeted Therapy for Gastrointestinal Cancers

“…MUC1 has also been reported to increase metastasis through the induction of platelet-derived growth factor (PDGF-A) expression by hypoxia inducible factor (HIF)1-α [ 56 ] and leads to epithelial-to-mesenchymal transition in pancreatic cancer [ 57 , 58 ]. MUC1 has also been shown to regulate function of transforming growth factor-β (TGF-β) and switch it from a tumor suppressor to a tumor promoter in PDA cells [ 59 , 60 ]. MUC1 is a prognostic factor that marks poor outcome in gastric cancer patients [ 61 ].…”