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Publications

Journal Article Epublish

PubMed: 40615400 DOI: 10.1038/s41419-025-07833-4

DSG2 promotes pancreatic cancer stem cell maintenance via support of tumour and macrophage cellular cross-talk.

Cell Death Dis 16(1):492

Authors: Faming Wang, Tao Sun, Ning Wang, Wei Wei, Ying Mei, Qiang Yan

Affiliations

  • The Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China.
  • Clinical Laboratory, The Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, Zhejiang, PR China.
  • The Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China.
  • Department of Hepatobiliary and Pancreatic Surgery, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou Central Hospital, Huzhou, China. Department of Surgery, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China. Department of Surgery, Affiliated Central Hospital of Huzhou University, Huzhou, China. Huzhou Key Laboratory of intelligent and digital precision Surgery, Huzhou, China.

Abstract

Pancreatic cancer stem cells (PCSCs) are a small population of cells in tumours that exhibit enhanced self-renewal and differentiation capabilities. CSCs proactively remodel the tumour microenvironment to maintain CSC stemness, which contributes to chemotherapy resistance. Compared with targeting PCSCs themselves, targeting the PCSC niche may be a novel strategy for pancreatic cancer (PC) therapy. Here, we found that DSG2, a member of the desmosomal cadherin family, is highly expressed in PCSCs. DSG2 upregulation is correlated with adverse outcomes in PC patients. DSG2 knockdown suppressed IL-4 and GM-CSF expression, which promoted the enrichment of tumour-associated macrophages to establish a supportive PCSC niche. Furthermore, we found that the IL-8/CXCR2 axis interacts with DSG2 to promote PCSC stemness and gemcitabine resistance by activating the Wnt/β-catenin pathway. These findings highlight the novel regulatory mechanism of DSG2 in PC, providing new targets for the development of therapeutics targeting PCSC niches.

MeSH

Cells, Pancreatic Neoplasms, Microscopy, Electron, Scanning Transmission, Macrophages, Neoplasms, Stem Cells, Maintenance, Therapeutics, Cell Death