Tumor cell-derived HSP47 promotes pancreatic Cancer metastasis via Homotrimeric collagen-mediated M2 macrophage polarization

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.