弥散性中线胶质瘤的侵袭和转移依赖细胞自主信号传导

Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling

NEURO-ONCOLOGY

影响因子:13.4

分区:医学1区 Top / 临床神经病学1区肿瘤学1区

发表日期:2024 Mar 04

作者: Marco Bruschi, Lilia Midjek, Yassine Ajlil, Stephanie Vairy, Manon Lancien, Samia Ghermaoui, Thomas Kergrohen, Maite Verreault, Ahmed Idbaih, Carlos Alberto Oliveira de Biagi, Ilon Liu, Mariella G Filbin, Kevin Beccaria, Thomas Blauwblomme, Stephanie Puget, Arnault Tauziede-Espariat, Pascale Varlet, Volodia Dangouloff-Ros, Nathalie Boddaert, Gwenael Le Teuff, Jacques Grill, Guillaume Montagnac, Nadia Elkhatib, Marie-Anne Debily, David Castel

DOI: 10.1093/neuonc/noad161

摘要

弥散性中线胶质瘤（DMG）是儿童肿瘤，诊断后2年生存几乎为零，主要表现为侵入中枢神经系统。为了控制局部生长和延缓疾病进展，所有患者均接受放疗。然而，DMG患者常发生远处进展。关于肿瘤侵袭的原因，目前主要集中在肿瘤微环境，但尚无已知的决定因素来预测侵袭程度。本研究利用患者来源的胶质瘤干细胞（GSC）建立患者特异的三维模型，以模拟个体间的侵袭行为并阐明细胞支持机制。我们发现，GSC模型在三维中反映了母体肿瘤的侵袭行为，证明DMG具有作为肿瘤细胞自主特性的侵袭能力。此外，我们区分了两种迁移模式：间充质型和阿米巴样型，并发现阿米巴样迁移与来自最具侵袭性肿瘤的GSC相关。通过转录组分析，无论是在类器官还是原发肿瘤中，侵袭性阿米巴样肿瘤被进一步定义为少突胶质细胞前体样，具有高度收缩的细胞骨架和降低的粘附能力，这主要由骨形态发生蛋白途径7（BMP7）过度表达驱动。最后，我们解析了在BMP7刺激下激活的MEK、ERK和Rho/ROCK激酶，作为可操作的靶点以控制肿瘤细胞运动。我们的研究发现提出了两条新治疗途径：首先，患者来源的GSC可以作为预测工具，用于患者分层和调整放疗策略；其次，基于自分泌和短程的BMP7相关信号成为抑制DMG扩散和转移的可药物靶点。

Abstract

Diffuse midline gliomas (DMG) are pediatric tumors with negligible 2-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease, all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness.In this study, we use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms.We show that GSC models in 3D mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished 2 modes of migration, mesenchymal and ameboid-like, and associated the ameboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive ameboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by crucial over-expression of bone morphogenetic pathway 7 (BMP7). Finally, we deciphered MEK, ERK, and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility.Our findings identify 2 new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for patient stratification in order to adapt irradiation strategies. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis.