Annexin A2\u2013STAT3\u2013Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma

Yuji Matsumoto,Kentaro Fujii,Keisuke Kaneda,Yoshihiro Otani,Yasuhiko Hattori,Kazuhiko Kurozumi,Keigo Makino,Atsushi Fujimura,Isao Date,Atsuhito Uneda,Yusuke Tomita,Nobushige Tsuboi,Tomotsugu Ichikawa

doi:10.1186/s40478-020-00916-7

Abstract

Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2–STAT3–OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2–STAT3–OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.

Highlights

Glioblastoma (GBM) is the most common and lethal primary brain malignancy in adults [23]
Genes regulated by annexin A2 (ANXA2) were defined as those meeting both of the following two criteria: Angiogenesis-1 genes were expressed at > 2-fold higher levels in J3T-2A cells than in J3T-2 cells, and Angiogenesis-2 genes were expressed at > 2-fold in J3T-1 cells compared with J3T1shA cells (Fig. 1a)
Clustering analysis of the genes using Ivy Glioblastoma Atlas Project (Ivy GAP) dataset revealed that the oncostatin M receptor (OSMR) had the most similar anatomical expression pattern to ANXA2 (Fig. 1d)

Summary

Introduction

Glioblastoma (GBM) is the most common and lethal primary brain malignancy in adults [23]. The defining aggressive hallmarks of GBM include abundant angiogenesis and marked proliferative and invasive behavior [12]. One reason is the marked intratumoral genetic heterogeneity and plasticity exhibited by GBM [26], Matsumoto et al Acta Neuropathologica Communications (2020) 8:42 including induction of a mesenchymal transition after therapy with cytotoxic agents [3]. This tumor frequently shows changes in biological features upon recurrence and progression. Elucidating the mechanisms underlying the phenotypic heterogeneity and transition is necessary to facilitate the development of curative therapies for GBM [12]

Methods

Results

Conclusion