Truncated O-Glycan-Bearing MUC16 Enhances Pancreatic Cancer Cells Aggressiveness via α4β1 Integrin Complexes and FAK Signaling

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  • Rajesh, Christabelle
    • Other Affiliation: University of Nebraska Medical Center
  • Sagar, Satish
    • Other Affiliation: University of Nebraska Medical Center
  • Rathinavel, Ashok Kumar
    • Other Affiliation: University of Nebraska Medical Center
  • Chemparathy, Divya Thomas
    • Other Affiliation: University of Nebraska Medical Center
  • Peng, Xianlu Laura
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Yeh, Jen Jen
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Hollingsworth, Michael A.
    • Other Affiliation: University of Nebraska Medical Center
  • Radhakrishnan, Prakash
    • Other Affiliation: University of Nebraska Medical Center
Abstract
  • Elevated levels of Mucin-16 (MUC16) in conjunction with a high expression of truncated O-glycans is implicated in playing crucial roles in the malignancy of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms by which such aberrant glycoforms present on MUC16 itself promote an increased disease burden in PDAC are yet to be elucidated. This study demonstrates that the CRISPR/Cas9-mediated genetic deletion of MUC16 in PDAC cells decreases tumor cell migration. We found that MUC16 enhances tumor malignancy by activating the integrin-linked kinase and focal adhesion kinase (ILK/FAK)-signaling axis. These findings are especially noteworthy in truncated O-glycan (Tn and STn antigen)-expressing PDAC cells. Activation of these oncogenic-signaling pathways resulted in part from interactions between MUC16 and integrin complexes (α4β1), which showed a stronger association with aberrant glycoforms of MUC16. Using a monoclonal antibody to functionally hinder MUC16 significantly reduced the migratory cascades in our model. Together, these findings suggest that truncated O-glycan containing MUC16 exacerbates malignancy in PDAC by activating FAK signaling through specific interactions with α4 and β1 integrin complexes on cancer cell membranes. Targeting these aberrant glycoforms of MUC16 can aid in the development of a novel platform to study and treat metastatic pancreatic cancer.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
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  • International Journal of Molecular Sciences
Journal volume
  • 23
Journal issue
  • 10
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  • 5459
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  • English
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  • 1422-0067

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