Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer

Divya Thomas, Satish Sagar, Xiang Liu, Hye Rim Lee, James A. Grunkemeyer, Paul M. Grandgenett, Thomas Caffrey, Kelly A. O'Connell, Benjamin Swanson, Lara Marcos-Silva, Catharina Steentoft, Hans H. Wandall, Hans Carlo Maurer, Xianlu Laura Peng, Jen Jen Yeh, Fang Qiu, Fang Yu, Ragupathy Madiyalakan, Kenneth P. Olive, Ulla MandelHenrik Clausen, Michael A. Hollingsworth, Prakash Radhakrishnan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3β oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

Original languageEnglish (US)
Pages (from-to)1557-1571
Number of pages15
JournalMolecular Therapy
Volume29
Issue number4
DOIs
StatePublished - Apr 7 2021

Keywords

  • COSMC
  • MUC16
  • Sialyl-Tn
  • Tn
  • mAb AR9.6
  • pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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