胰管导管腺癌（PDAC）经常转移至腹膜，这导致了恶性预后。癌细胞的可塑性促进了转移，然而其被微环境调节的机制尚未完全理解。在这里，我们展示了细胞外基质中透明质酸和蛋白聚糖链接蛋白-1（HAPLN1）的存在增强了肿瘤细胞的可塑性和PDAC的转移。生物信息学分析表明HAPLN1表达在PDAC的基底亚型中富集，并且与更糟糕的患者总体生存有关。在腹腔癌转移的小鼠模型中，HAPLN1诱导的免疫调节有利于更加宽容的微环境，加速了肿瘤细胞在腹膜的传播。机械上，HAPLN1通过上调肿瘤坏死因子受体2（TNFR2），促进TNF介导的透明质酸（HA）产生的上调，从而促进EMT，干细胞状态，侵袭和免疫调节。细胞外HAPLN1改变了癌细胞和成纤维细胞，使它们更具免疫调节性。因此，我们将HAPLN1识别为PDAC的预后标志物和腹膜转移的驱动因素。©2023，作者（们）。

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.© 2023. The Author(s).