Key points are not available for this paper at this time.
The metastatic progression of pancreatic ductal adenocarcinoma (PDAC) is governed by dynamic interactions between cancer cells and immune cells within the tumor microenvironment; yet the underlying mechanisms remain largely elusive. Here, single-cell analysis identifies the collagen-specific chaperone HSP47 as predominantly expressed in PDAC epithelial cells. High HSP47 expression drives liver metastasis and serves as a predictor of poor survival in PDAC patients. Mechanistically, tumor cell-derived HSP47 promotes PDAC metastasis by creating an immunosuppressive microenvironment. It drives the secretion of a homotrimeric, tumor-specific form of collagen I (α1/α1/α1, also referred to as COL1) into the extracellular matrix (ECM) (rather than modulating its protein expression), which is essential for HSP47-mediated immunosuppression in PDAC. The accumulated COL1 polarizes tumor-associated macrophages (TAMs) toward an immunosuppressive M2 phenotype via the integrin α2β1/MAPK/ERK signaling pathway. These reprogrammed M2 macrophages, in turn, establish a feedforward loop by enhancing epithelial-mesenchymal transition (EMT) in PDAC cells through macrophage-derived Phosphoglycerate mutase 1 (PGAM1) in an ACTG1-dependent manner (Actin Gamma 1, ACTG1). In summary, our findings highlight the critical role of the HSP47-COL1-PGAM1 axis in PDAC metastasis, unveiling a previously unrecognized pro-metastatic regulatory circuit that provides mechanistic insights into PDAC progression.
Ling et al. (Fri,) studied this question.