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

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.