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Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis

Rakesh Bhatia1, Jawed Akhtar Siddiqui1,2, Koelina Ganguly1

  • 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.

Oncogene
|January 9, 2023
PubMed

Insights

Mucin4 (MUC4) protein promotes pancreatic cancer by stabilizing epidermal growth factor receptor (EGFR) signaling. Depleting MUC4 delays tumor formation and reduces EGFR activity, offering a new therapeutic target for pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mucin4 (MUC4) expression is an early event in pancreatic intraepithelial neoplasia (PanIN), coinciding with epidermal growth factor receptor (EGFR) signaling, which is crucial for Kras-driven pancreatic ductal adenocarcinoma (PDAC).
  • The precise mechanisms sustaining EGFR signaling in early PanIN lesions remain unclear.

Purpose of the Study:

  • To investigate the role of MUC4 in PDAC development and EGFR signaling using a conditional knockout murine model.
  • To elucidate the molecular interaction between MUC4 and EGFR in PDAC pathogenesis.

Main Methods:

  • Generation of a Muc4 conditional knockout murine model (KPCM4-/-) with K-ras and p53 mutations.
  • Analysis of PanIN lesion formation, EGFR and ERK1/2 phosphorylation, and Sox9 expression in KPCM4-/- mice.
  • Biochemical assays to determine the interaction interface between MUC4 and EGFR.

Main Results:

  • Muc4 depletion significantly delayed PanIN lesion formation in KPCM4-/- mice.
  • Reduced phosphorylation of EGFR (Y1068) and ERK1/2 (T202/Y204) was observed in PanIN lesions of KPCM4-/- mice.
  • Decreased Sox9 expression indicated impaired acinar-to-ductal metaplasia in MUC4-depleted cells, and MUC4 was shown to prevent EGFR ubiquitination and degradation.

Conclusions:

  • MUC4 interacts with EGFR, stabilizing its signaling pathway by preventing degradation.
  • Targeting the MUC4-EGFR interaction interface presents a potential therapeutic strategy for PDAC and other MUC4-expressing cancers.

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