Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence.
Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence.
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DOI：
10.1158/1541-7786.mcr-21-0284
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Xia S
中科院分区：
文献类型：
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作者：
Zhan D;Ma D;Wei S;Lal B;Fu Y;Eberhart C;Laterra J;Ying M;Li Y;Meeker A;Lopez-Bertoni H;Xia S
杂合性IDH R132H突变(IDH1R132H/WT)是胶质瘤发生的早期事件。临床上，携带突变IDH1的胶质瘤患者对抗肿瘤治疗有更好的反应。然而，IDH1突变促进胶质瘤发生和治疗反应的机制仍然不清楚。在此，我们报告了衰老与突变型IDH1胶质瘤细胞治疗反应的改善有关。在胶质瘤细胞中敲入IDH1R132H/WT可通过DNA损伤机制显著增强替莫唑胺和辐射对胶质瘤细胞的衰老作用。我们进一步询问衰老是否在IDH1R132H/WT诱导的胶质瘤形成中起作用。与ATRX基因敲除和p53/Rb缺失一起，IDH1R132H/WT转化非肿瘤性人类星形胶质细胞在小鼠脑内形成肿瘤。进一步的鉴定表明，这些癌前细胞中的一部分经历了衰老样表型变化，包括细胞形态扁平和增大，衰老标志物表达增加，细胞增殖减少，细胞周期停滞在G2/M期。机制研究表明，胶质瘤驱动基因(P53/Rb/IDH1/ATRX)的组合显著增加了衰老细胞的DNA损伤，并激活了DNA损伤反应通路ATR/ATR和Chk1/Chk2。为了确定衰老细胞如何驱动肿瘤的形成，我们研究了非细胞自主机制，如衰老相关分泌表型(SASP)，一组与肿瘤允许的微环境有关的促炎和组织重塑因子。我们发现携带P53/Rb/ATRX缺失和IDH1R132H/WT的星形胶质细胞通过表观遗传机制上调SASP中的关键因子。我们的工作表明，在抗肿瘤治疗后，专门消除衰老细胞的药物可能有助于杀死癌前细胞和衰老的肿瘤细胞。
Heterozygous IDH R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, glioma patients carrying mutant IDH1 respond better to anti-tumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced glioma cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed non-neoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these pre-cancerous cells underwent senescence-like phenotypic changes, including flat and enlarged cell morphology, increased senescence marker expression, decreased cell proliferation, and cell cycle arrest at the G2/M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNA damage response pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non-cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of pro-inflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill pre-cancerous cells and senescent tumor cells following anti-tumor therapies.