Radiation-induced senescence in the brain microenvironment: Implications for glioblastoma recurrence and therapy

摘要 胶质母细胞瘤（GBM）是侵袭性和放射抗性的脑癌， 是迫切需要的。GBM患者用50-60戈伊的电离辐射（IR）治疗，同时和 替莫唑胺（TMZ）辅助化疗。放射仍然是最有效的治疗方法 尽管这些肿瘤不可避免地复发，并且复发的肿瘤对标准的化疗具有高度抗性， 疗法治疗的任何改进都需要更好地理解GBM复发的基础， 复发性肿瘤的治疗抗性。我们实验室用转基因小鼠模型发表的研究表明， 确定IR是潜在的神经胶质瘤，并且辐射暴露后产生的神经胶质瘤的标志是 基因组改变，如促进癌症干细胞表型的MET扩增， 抗辐射性这增加了放射治疗引起的GBM细胞遗传改变的可能性。 可能使复发的肿瘤对进一步的治疗干预难治。来自我们实验室的令人兴奋的新结果 显示辐射也促进衰老相关分泌表型（SASP）的发展 在脑微环境中，通过分泌生长因子如HGF促进肿瘤发展 （MET的配体）。这表明，辐射诱导的正常脑细胞衰老在附近的 肿瘤可以改变微环境，促进肿瘤复发和放射抵抗。平移地 我们实验室的重要结果表明，新的“衰老清除”药物可以选择性地清除衰老的星形胶质细胞， 并减轻SASP的促肿瘤作用。我们假设放射治疗引起的 GBM细胞中的遗传改变（例如，MET扩增）与衰老相关的 大脑微环境的变化（例如，HGF分泌）促进肿瘤复发， 抗辐射性我们建议分析“senolytics”是否可以选择性地杀死衰老的脑细胞， 由于放射治疗，从而使GBM放射增敏并延迟肿瘤复发。目前迫切 需要实验策略来理解GBM中的这种“获得性”治疗耐药机制， 发展翻译方法。我们已经开发了新的患者来源的异种移植物（PDX）和同基因 GBM复发模型。使用这些模型和人类GBM标本，我们将 研究（1）放射治疗引起的MET扩增如何通过重编程转录因子 如SOX 2和OLIG 2，产生具有增强的DNA修复能力的癌症干细胞，（2）如何分泌 肿瘤促进因子，如MET配体HGF，通过衰老的星形胶质细胞可能促进生长， MET扩增的GBM细胞的辐射抗性，以及（3）GBM与其细胞之间的合作如何？ 衰老的微环境可以用“衰老清除”药物来消除，以改善GBM的结果 疗法该项目可以导致开发有效的策略来治疗GBM， 考虑到放射治疗期间GBM细胞和脑微环境的变化。

Abstract Glioblastomas (GBM) are aggressive and radioresistant brain cancers for which better therapeutic approaches are desperately needed. GBM patients are treated with 50-60 Gy of ionizing radiation (IR), and concurrent and adjuvant chemotherapy with temozolomide (TMZ). Radiation still remains the most effective therapeutic modality for GBM, yet these tumors inevitably recur, and the recurrent tumors are highly resistant to standard therapy. Any improvement in therapy would require a better understanding of the basis of GBM recurrence and therapy resistance of the recurrent tumor. Published research from our lab with transgenic mouse models has established that IR is potently gliomagenic, and that gliomas arising after radiation exposure are marked by genomic alterations such as MET amplification which promote a cancer stem cell phenotype and radioresistance. This raises the possibility that genetic alterations in GBM cells wrought by radiation therapy could render the recurrent tumor refractory to further therapeutic intervention. Exciting new results from our lab show that radiation also promotes the development of a senescence-associated secretory phenotype (SASP) in the brain microenvironment which promotes tumor development via secretion of growth factors like HGF (ligand for MET). This suggests that radiation-induced senescence of normal brain cells in the vicinity of the tumor could alter the microenvironment to promote tumor recurrence and radioresistance. Translationally significant results from our lab show that novel “senolytic” drugs can selectively eliminate senescent astrocytes in the brain and mitigate the pro-tumorigenic effects of SASP. We hypothesize that radiotherapy-induced genetic alterations in GBM cells (e.g., MET amplification) cooperate with senescence-associated changes in the brain microenvironment (e.g., HGF secretion) to promote tumor recurrence and radioresistance. We propose to analyze if “senolytics” can selectively kill senescent brain cells arising due to radiotherapy, thereby radiosensitizing GBM and delaying tumor recurrence. There is an urgent need for experimental strategies to understand such “acquired” therapy-resistance mechanisms in GBM and develop translational approaches. We have developed novel patient-derived xenograft (PDX) and syngeneic models of GBM recurrence for this purpose. Using these models, and human GBM specimens, we will investigate (1) how MET amplification caused by radiotherapy might, via reprogramming transcription factors like SOX2 and OLIG2, generate cancer stem cells with augmented DNA repair capabilities, (2) how secretion of tumor promoting factors, like the MET ligand HGF, by senescent astrocytes might promote growth and radioresistance of GBM cells with MET amplification, and (3) how cooperation between the GBM and its senescent microenvironment can be negated with “senolytic” drugs in order to improve the outcome of GBM therapy. This project can lead to the development of effective strategies to treat GBM that take into consideration both changes to the GBM cell and the brain microenvironment during radiotherapy.