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

摘要 胶质母细胞瘤(GBM)是侵袭性和放射抵抗的脑癌，有较好的治疗方法。 都是非常需要的。GBM患者接受50-60GY的电离辐射(IR)治疗，并同时进行 替莫唑胺(TMZ)辅助化疗。放射治疗仍然是最有效的治疗方法 GbM的治疗方式，然而这些肿瘤不可避免地复发，并且复发的肿瘤对标准高度抵抗。 心理治疗。在治疗方面的任何改进都需要更好地了解GBM复发的基础和 复发肿瘤的治疗抵抗。我们实验室发表的转基因小鼠模型研究已经完成 已证实IR具有潜在的神经胶质瘤生成作用，而辐射暴露后出现的胶质瘤的特点是 基因组改变，如MET扩增，促进癌症干细胞表型和 抗辐射能力。这增加了放射治疗引起的GBM细胞的基因改变的可能性 可能使复发的肿瘤难以进行进一步的治疗。来自我们实验室的令人振奋的新结果 表明辐射还促进衰老相关分泌表型(SASP)的发展 在大脑微环境中，通过分泌HGF等生长因子促进肿瘤的发展 (MET的配基)。这表明，辐射诱导的正常脑细胞的衰老 肿瘤可改变微环境，促进肿瘤复发和放射抵抗。翻译过来就是 我们实验室的重要结果表明，新型的“抗衰老”药物可以选择性地消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细胞的基因改变(如MET扩增)与衰老相关 改变大脑微环境(例如，HGF分泌)以促进肿瘤复发和 抗辐射能力。我们建议分析“感觉剂”是否可以选择性地杀死衰老的脑细胞。 由于放射治疗，从而对基底膜具有放射增敏作用，延缓肿瘤复发。有一件急事 有必要采取实验策略来了解这种“获得性”治疗耐药机制 开发翻译方法。我们开发了新的患者来源的异种移植(PDX)和同基因移植 用于此目的的基底膜复发模型。使用这些模型和人类基底膜样本，我们将 研究(1)放射治疗引起的MET扩增如何通过重新编程转录因子 像SOX2和OLIG2一样，产生具有增强DNA修复能力的癌症干细胞，(2)如何分泌 衰老的星形胶质细胞分泌促肿瘤因子，如MET配体HGF，可能会促进生长和 MET扩增的GBM细胞的辐射抗性以及(3)GBM与ITS之间的协同作用 抗衰老药物可改善肾小球基底膜的转归 心理治疗。该项目可以导致制定有效的策略来治疗GBM，包括 同时考虑放射治疗对基底膜细胞和脑微环境的影响。

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.