MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2-Associated Cell Adhesion

Saravanakumar Marimuthu, Imayavaramban Lakshmanan, Sakthivel Muniyan, Shailendra K. Gautam, Rama Krishna Nimmakayala, Sanchita Rauth, Pranita Atri, Ashu Shah, Namita Bhyravbhatla, Kavita Mallya, Paul M. Grandgenett, Michael A. Hollingsworth, Kaustubh Datta, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, as it commonly metastasizes to the liver resulting in an overall poor prognosis. However, the molecular mechanism involved in liver metastasis remains poorly understood. Here, we aimed to identify the MUC16-mediated molecular mechanism of PDAC-liver metastasis. Previous studies demonstrated that MUC16 and its C-terminal (Cter) domain are involved in the aggressiveness of PDAC. In this study, we observed MUC16 and its Cter expression significantly high in human PDAC tissues, PDAC organoids, and metastatic liver tissues, while no expression was observed in normal pancreatic tissues using IHC and immunofluorescence (IFC) analyses. MUC16 knockdown in SW1990 and CD18/HPAF PDAC cells significantly decreased the colony formation, migration, and endothelial/p-selectin binding. In contrast, MUC16-Cter ectopic overexpression showed significantly increased colony formation and motility in MiaPaCa2 pancreatic cancer cells. Interestingly, MUC16 promoted cell survival and colonization in the liver, mimicking an ex vivo environment. Furthermore, MUC16 enhanced liver metastasis in the in vivo mouse model. Our integrated analyses of RNA-sequencing suggested that MUC16 alters Neuropilin-2 (NRP2) and cell adhesion molecules in pancreatic cancer cells. Furthermore, we identified that MUC16 regulated NRP2 via JAK2/STAT1 signaling in PDAC. NRP2 knockdown in MUC16-overexpressed PDAC cells showed significantly decreased cell adhesion and migration. Overall, the findings indicate that MUC16 regulates NRP2 and induces metastasis in PDAC.

Original languageEnglish (US)
Pages (from-to)1208-1221
Number of pages14
JournalMolecular Cancer Research
Volume20
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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