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

Grover, P.; Nath, S.; Bose, M.; Sanders, A. J.; Brouwer, C.; Fnu, N.; Zhou, R.; Yazdanifar, M.; Ahmed, M.; Wu, S.-t.; Truman, A. W.; Mukherjee, P.

doi:10.1101/2020.04.29.068577

bioRxiv · 10.1101/2020.04.29.068577

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

Grover, P.·Nath, S.·Bose, M.·Sanders, A. J.·Brouwer, C.·Fnu, N.·Zhou, R.·Yazdanifar, M.·Ahmed, M.·Wu, S.-t.·Truman, A. W.·Mukherjee, P.

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-{beta}) is a cytokine that switches from a tumor-suppressor 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-{beta} functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-{beta}RII and negatively to TGF-{beta}RI receptors. In response to TGF-{beta}1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-{beta}1 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-{beta} pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-{beta}s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-{beta}-targeted therapies.

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Grover, P., Nath, S., Bose, M., Sanders, A. J., Brouwer, C., Fnu, N., Zhou, R., Yazdanifar, M., Ahmed, M., Wu, S.-t., Truman, A. W., Mukherjee, P.. 2020-05-01. Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma. https://doi.org/10.1101/2020.04.29.068577

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