Department of Neurosurgery, Daping Hospital, The Army Medical University, Chongqing, China.
Mol Carcinog. 2024 Jul;63(7):1235-1247. doi: 10.1002/mc.23720. Epub 2024 Mar 22.
Glioblastoma (GBM) is the most aggressive brain tumor type with worse clinical outcome due to the hallmarks of strong invasiveness, high rate of recurrence, and therapeutic resistance to temozolomide (TMZ), the first-line drug for GBM, representing a major challenge for successful GBM therapeutics. Understanding the underlying mechanisms that drive GBM progression will shed novel insight into therapeutic strategies. Receptor-type tyrosine-protein phosphatase S (PTPRS) is a frequently mutated gene in human cancers, including GBM. Its role in GBM has not yet been clarified. Here, inactivating PTPRS mutation or deficiency was frequently found in GBM, and deficiency in PTPRS significantly induced defects in the G2M checkpoint and limited GBM cells proliferation, leading to potent resistance to TMZ treatment in vitro and in vivo. Surprisingly, loss of PTPRS triggered an unexpected mesenchymal phenotype that markedly enhances the migratory capabilities of GBM cells through upregulating numerous matrix metalloproteinases via MAPK-MEK-ERK signaling. Therefore, this work provides a therapeutic window for precisely excluding PTPRS-mutated patients who do not respond to TMZ.
胶质母细胞瘤（GBM）是侵袭性最强的脑肿瘤类型，由于其具有很强的侵袭性、高复发率以及对替莫唑胺（TMZ）的治疗抵抗等特征，而 TMZ 是 GBM 的一线药物，这给 GBM 的成功治疗带来了重大挑战。了解驱动 GBM 进展的潜在机制将为治疗策略提供新的见解。受体型酪氨酸蛋白磷酸酶 S（PTPRS）是人类癌症中经常发生突变的基因，包括 GBM。但其在 GBM 中的作用尚未阐明。在这里，PTPRS 失活或缺失突变在 GBM 中经常被发现，并且 PTPRS 的缺失显著诱导了 G2M 检查点缺陷，并限制了 GBM 细胞的增殖，导致体外和体内对 TMZ 治疗产生强大的耐药性。令人惊讶的是，PTPRS 的缺失触发了一种意想不到的间充质表型，通过 MAPK-MEK-ERK 信号通路显著上调许多基质金属蛋白酶，从而显著增强了 GBM 细胞的迁移能力。因此，这项工作为精确排除对 TMZ 无反应的 PTPRS 突变患者提供了一个治疗窗口。
