HAPLN1 potentiates peritoneal metastasis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favored a more permissive microenvironment, which accelerated the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promoted TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modified cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identified HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC. Overall design: 15 samples in total, 3x tumor cells from solid KPC tumors, 3x tumor cells from solid KPC HAPLN1 tumors, 3x tumor cells from ascites of KPC HAPLN1, 3x fibroblasts from KPC tumors, 3x fibroblasts from KPC HAPLN1 tumors.