4.7 Article

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

Journal

MOLECULAR THERAPY
Volume 29, Issue 4, Pages 1557-1571

Publisher

CELL PRESS
DOI: 10.1016/j.ymthe.2020.12.029

Keywords

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Funding

  1. National Cancer Institute at the National Institutes of Health [R01 CA208108, R01CA199064]
  2. NIH/SPORE Carrier Development Award [P50CA127297, NE-DHHS/LB506]
  3. Pancreatic Cancer Detection Consortium [5U01CA210240]
  4. Tumor Microenvironment Network [U54 CA163120, R50CA211462]
  5. Danish National Research Foundation [DNRF107]
  6. NIH/SPORE [P50CA127297, P01CA217798]

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Aberrant expression of MUC16 is associated with PDAC progression, tumor subtypes, metastasis and patient survival. MUC16 enhances tumor malignancy through ErB receptor-mediated oncogenic signaling pathways. Treatment with mAb AR9.6 reduces metastasis and tumor growth in PDAC-bearing mice.
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 GSK3boncogenic 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 MUC16induced 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.

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