HAPLN1 is a driver for peritoneal carcinomatosis in pancreatic cancer

Abstract

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 hyaluronic acid synthesis and signaling, promoted adoption of a highly plastic cancer cell state, facilitating EMT, stemness, invasion and immunomodulation in a paracrine manner. Extracellular HAPLN1 modifies cancer cells as well as fibroblasts, rendering them immunomodulatory. We identify HAPLN1 as a prognostic marker and a driver for peritoneal metastasis in PDAC.

Therapeutic potential of TNFR2 agonists: a mechanistic perspective

“…Blockade of TNFR2 has been shown to alleviate anti-PD-1-induced hepatic inflammation in mouse hepatic carcinoma, even infiltration of Tregs was also decreased (131). Moreover, TNFR2 signaling in some tumor cell types also contribute to tumor progression (132,133), so the potentially undesirable effect of TNFR2 agonistic antibody should be considered. Thus, tissue-specific responses are also an important factor that needs to be considered in TNFR2 agonist therapy.…”

The molecular biology of peritoneal metastatic disease

“…Discrepant results on CMS distribution in PM samples have also been reported, which are most likely explained by the CMS classification method (Barriuso et al , 2021). In PDAC, no relation between molecular subtype and dissemination pattern is described yet, although HAPLN1 was found to be a driver for PM in PDAC, and associated with the poor prognosis basal subtype (preprint: Wiedmann et al , 2022). In contrast to PM, liver metastases are mostly classified as the epithelial CMS2 subtype in CRC (Pitroda et al , 2018) and are associated with the MSS/TP53‐ and MSI subtypes in GC (Cristescu et al , 2015).…”