TY - JOUR
T1 - Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer
AU - Thomas, Divya
AU - Sagar, Satish
AU - Liu, Xiang
AU - Lee, Hye Rim
AU - Grunkemeyer, James A.
AU - Grandgenett, Paul M.
AU - Caffrey, Thomas
AU - O'Connell, Kelly A.
AU - Swanson, Benjamin
AU - Marcos-Silva, Lara
AU - Steentoft, Catharina
AU - Wandall, Hans H.
AU - Maurer, Hans Carlo
AU - Peng, Xianlu Laura
AU - Yeh, Jen Jen
AU - Qiu, Fang
AU - Yu, Fang
AU - Madiyalakan, Ragupathy
AU - Olive, Kenneth P.
AU - Mandel, Ulla
AU - Clausen, Henrik
AU - Hollingsworth, Michael A.
AU - Radhakrishnan, Prakash
N1 - Funding Information:
This work was supported by the National Cancer Institute at the National Institutes of Health R01 CA208108, NIH/SPORE Carrier Development Award (P50CA127297), and NE-DHHS/LB506 to P.R.; NIH/SPORE P50CA127297, Program Project Grant P01CA217798, Early Detection Research Network 5U01CA111294, Pancreatic Cancer Detection Consortium 5U01CA210240, and Tumor Microenvironment Network U54 CA163120 to M.A.H. and R50CA211462 to P.M.G.; The National Cancer Institute at the National Institutes of Health R01CA199064 to J.J.Y.; and The Danish National Research Foundation DNRF107 to H.C. Also, we thank Jessica Odvody, Premila Leiphrakpam, Krishti Sabloak, and Philamon Leon for their technical assistance. P.R. conceived and supervised the study. D.T. S.S. and X.L. performed most of the in vitro and in vivo experiments. H.-R.L. J.A.G. P.M.G. and T.C. performed orthotopic tumor studies. B.S. scored the immunohistochemical staining. L.M.-S. H.C. C.S. and H.H.W. provided COSMC KO PDAC cells and performed anti-MUC16 mAb epitope mapping studies. H.C.M. and K.P.O. performed RNA sequencing analysis. X.L.P. and J.J.Y. performed tumor sub-type analysis with MUC16 expression. F.Q. and F.Y. performed biostatistical analysis. R.M. provided AR9.6 mAb expressing clones. U.M. provided anti-MUC16 antibodies (5E11 and 5B9) for the study. M.A.H. analyzed the data. D.T. M.A.H. and P.R wrote the manuscript. 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.
Publisher Copyright:
© 2020 The American Society of Gene and Cell Therapy
PY - 2021/4/7
Y1 - 2021/4/7
N2 - 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.
AB - 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.
KW - COSMC
KW - mAb AR9.6
KW - MUC16
KW - pancreatic ductal adenocarcinoma
KW - Sialyl-Tn
KW - Tn
UR - http://www.scopus.com/inward/record.url?scp=85099629651&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2020.12.029
DO - 10.1016/j.ymthe.2020.12.029
M3 - Article
C2 - 33359791
AN - SCOPUS:85099629651
SN - 1525-0016
VL - 29
SP - 1557
EP - 1571
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -
