Serum Mac2-binding Protein Glycosylated Isomer (M2BPGi) As a Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma: ICAFs-derived M2BPGi Drives Tumor Invasion

Overview

Journal J Gastroenterol

Specialty Gastroenterology

Date 2024 Dec 11

PMID 39661112

Authors

Naotaka Kugiyama

Katsuya Nagaoka

Rin Yamada

Takehisa Watanabe

Hajime Yamazaki

Shinya Ushijima

Fumiya Otsuka

Yukiko Uramoto

Hajime Iwasaki

Motohiro Yoshinari

Shunpei Hashigo

Hiromitsu Hayashi

Takatsugu Ishimoto

Yoshihiro Komohara

Yasuhito Tanaka

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Mac2-binding protein glycosylated isomer (M2BPGi), a known biomarker for liver fibrosis, is also elevated in other fibrotic tissues. However, its role in PDAC remains unexplored. This study investigates the potential of M2BPGi as a prognostic biomarker for PDAC and elucidates its role in cancer progression.

Methods: We analyzed serum M2BPGi levels in 83 PDAC patients and 60 healthy controls, examining the relationship with clinical outcomes. Tissue immunostaining and in vitro experiments were conducted to investigate M2BPGi-secreting cells and its role.

Results: Serum M2BPGi levels were significantly higher in PDAC patients than in controls (0.98 vs. 0.59, p < 0.0001). Notably, elevated serum M2BPGi was associated with worse progression-free survival (144 days vs. 260 days, p = 0.017) and overall survival (OS) (245 days vs. 541 days, p < 0.001) following chemotherapy. Multivariable Cox regression analysis further confirmed that a high serum M2BPGi level is an independent risk factor for OS (HR: 2.44, 95% CI 1.26-4.74, p = 0.008). Immunostaining revealed that M2BPGi is secreted by both cancer cells and cancer-associated fibroblasts (CAFs), with high M2BP expression in CAFs correlating with poor prognosis. Furthermore, M2BPGi-secreting CAFs exhibited characteristics of inflammatory CAFs. M2BPGi directly activated mTOR signaling and epithelial-mesenchymal transition in PDAC cells, enhancing their invasive and migratory capabilities.

Conclusions: Our findings identify M2BPGi as a promising prognostic biomarker for PDAC. Moreover, we demonstrate that inflammatory CAFs promote tumor invasion and contribute to poor outcomes by secreting M2BPGi, revealing a novel mechanism of PDAC progression.

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