Nature communications · 2023
HAPLN1 potentiates peritoneal metastasis in pancreatic cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Wiedmann Lena, De Angelis Rigotti Francesca, Vaquero-Siguero Nuria, Donato Elisa, Espinet Elisa, Moll Iris, Alsina-Sanchis Elisenda, Bohnenberger Hanibal, Fernandez-Florido Elena, Mülfarth Ronja, Vacca Margherita, Gerwing Jennifer, Conradi Lena-Christin, Ströbel Philipp, Trumpp Andreas, Mogler Carolin, Fischer Andreas, Rodriguez-Vita Juan
Аннотация
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 favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.