HAPLN1 potentiates peritoneal metastasis 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 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.

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

“…An upregulation of HAPLN1 has been reported in pancreatic cancer and malignant pleural mesothelioma [108], while its expression is lost in CRC [110]. HAPLN1 expression is enriched in basal subtype PDAC, which is associated with poor OS and peritoneal metastasis [107]. An upregulation of HAPLN1 in cancer-associated fibroblasts (CAF) has been reported in GC, which is associated with an aggressive phenotype, poor prognosis, and tumour progression [109].…”

“…Pancreas cancer [107], malignant pleural mesothelioma [108], lung cancer [109] Colorectal cancer [110], malignant gliomas [111] HAPLN2 Malignant gliomas [111] HAPLN3 Breast cancer [112,113], clear cell renal cell cancer [114] Advanced skin cutaneous melanoma [115], cutaneous melanoma [116] Gene methylation: prostate cancer [117] and de novo metastatic prostate cancer [118] HAPLN4 Malignant gliomas [111]…”

“…HAPLN1 is the most-studied HAPLN family member in terms of metastasis. Its expression is enriched in basal PDAC subtypes and is associated with poor OS [107]. Upregulated HAPLN promotes peritoneal dissemination [107] and elevated expression of HAPLN1 in CAFs is associated with an aggressive phenotype, poor prognosis, and tumour progression in GC [109].…”

“…Its expression is enriched in basal PDAC subtypes and is associated with poor OS [107]. Upregulated HAPLN promotes peritoneal dissemination [107] and elevated expression of HAPLN1 in CAFs is associated with an aggressive phenotype, poor prognosis, and tumour progression in GC [109]. HAPLN1 can increase the permeability of lymphatic vessels by downregulating VE-cadherin in lymphatic ECs, which may contribute to in-transit metastases in melanoma, but this is associated with an increased risk of visceral metastases [282].…”

“…Understanding the aging-related changes of ECM in melanoma and the response to immune checkpoint inhibitors may help to improve the efficacy of immunotherapy. HAPLN1 is also associated with peritoneal metastasis in the pancreatic cancer [107], but its expression can inhibit lymph node metastasis in melanoma [282], suggesting context-specific functionality. Apart from HAPLN1, clinical data analysis showed that HAPLN3 overexpression was related to breast cancer metastasis [112] and its level was closely related to the depth of tumour invasion, lymph node invasion and distant metastases in ccRCC [114].…”