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Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Apr 07; Vol. 29 (4), pp. 1557-1571. Date of Electronic Publication: 2020 Dec 25. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests M.A.H. and P.R. have an equity interest in OncoCare Therapeutics. R.M. is employed by Quest PharmaTech and has an equity interest in this company. All other authors declare no competing interests.<br /> (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma immunology
Adenocarcinoma pathology
Animals
Antibodies, Monoclonal pharmacology
CA-125 Antigen immunology
Carcinogenesis immunology
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal immunology
Carcinoma, Pancreatic Ductal pathology
Cell Line, Tumor
Cell Proliferation genetics
Disease Progression
ErbB Receptors antagonists & inhibitors
ErbB Receptors immunology
Gene Expression Regulation, Neoplastic drug effects
Humans
Membrane Proteins antagonists & inhibitors
Membrane Proteins immunology
Mice
Neoplasm Metastasis
Protein Isoforms genetics
Protein Isoforms immunology
Signal Transduction
Adenocarcinoma drug therapy
CA-125 Antigen genetics
Carcinogenesis genetics
Carcinoma, Pancreatic Ductal drug therapy
ErbB Receptors genetics
Membrane Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 29
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 33359791
- Full Text :
- https://doi.org/10.1016/j.ymthe.2020.12.029