弥漫性中线神经胶质瘤入侵和转移依赖于细胞自主信号传导
Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling
影响因子:13.40000
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
摘要
弥漫性中线神经胶质瘤（DMG）是儿科肿瘤，诊断后的2年生存率可忽略不计，其特征是它们渗入中枢神经系统的能力。为了控制局部生长并减缓疾病，所有患者都接受了放射疗法。但是，DMG患者经常发生遥远的进展。目前关于导致肿瘤浸润的原因的目前线索主要是围绕肿瘤微环境，但目前尚无已知的决定因素来预测侵入性的程度。在这项研究中，我们使用患者衍生的神经胶质瘤干细胞（GSC）来创建患者特异性的3D AFAT，以模拟跨性别的射击和透明的镜子。肿瘤，因此证明了DMG作为肿瘤细胞的自主特征的能力。此外，我们区分了2种迁移模式，间充质和类似体性的模式，并将其类似体的模态与来自最具侵入性肿瘤的GSC相关联。我们使用器官和原发性肿瘤的转录组学，进一步将浸润性氨基骨状肿瘤表征为少突胶质细胞祖细胞，具有高收缩性细胞骨架，并降低了由骨形态学途径7（BMP7）的至关重要的过度表达所驱动的粘附能力。最后，我们破译了MEK，ERK和RHO/ROCK激酶，将BMP7刺激的下游激活为控制肿瘤细胞运动性的可行靶标。我们的发现确定了2种新的治疗途径。首先，患者来源的GSC代表了患者分层的预测工具，以适应辐射策略。其次，自分泌和短距离BMP7相关的信号传导成为防止DMG扩散和转移的可药物目标。
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.