Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Department of Pathology, All India Institute of Medical Science, New Delhi, India.
Clin Cancer Res. 2018 Mar 15;24(6):1448-1458. doi: 10.1158/1078-0432.CCR-17-1901. Epub 2017 Dec 20.
Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole-exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways. WES of different astrocytoma samples ( = 42; Indian cohort) was carried out and compared with that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines, and mouse xenograft models were used for functional characterization of calcitonin receptor (CALCR) and establish it as a therapeutic target. A similar mutation spectrum between the Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "neuroactive ligand-receptor interaction" pathway ( = 23; 9.54%) that have significantly poor prognosis ( < 0.0001). Furthermore, GBMs with mutated calcitonin receptor () or reduced transcript levels predicted poor prognosis. Exogenously added calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss of function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes Furthermore, calcitonin inhibited patient-derived neurosphere growth and glioma tumor growth in a mouse model. We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM. .
尽管对生物学的理解有了重大进展，但胶质母细胞瘤（GBM）的预后仍然很差。目的是对印度的神经胶质瘤进行全外显子组测序（WES），并与 TCGA 整合，以找到具有临床相关性的突变途径。对不同的星形细胞瘤样本（= 42；印度队列）进行了 WES，并与 TCGA 队列进行了比较。对来自印度和 TCGA 队列的突变基因进行了综合分析，以确定与遗传改变相关的途径的生存关联。患者来源的神经胶质瘤干细胞、神经胶质瘤细胞系和小鼠异种移植模型用于降钙素受体（CALCR）的功能特征鉴定，并将其确立为治疗靶标。印度队列和 TCGA 队列之间显示出相似的突变谱。综合分析确定了具有缺陷的“神经活性配体-受体相互作用”途径的 GBM（= 23；9.54%），其预后明显较差（< 0.0001）。此外，CALCR 突变或转录水平降低的 GBM 预测预后不良。外源性添加降钙素（CT）以 CALCR 依赖性方式抑制神经胶质瘤细胞的各种特性和原癌信号通路。CALCR 中的患者来源突变消除了这些功能，功能丧失的程度与患者的生存呈负相关。野生型 CALCR，但不是突变版本，抑制了永生星形细胞中 Ras 介导的转化。此外，降钙素抑制了患者来源的神经球生长和小鼠模型中的神经胶质瘤肿瘤生长。我们证明 CT-CALCR 信号轴是神经胶质瘤中的一个重要肿瘤抑制途径，并将 CALCR 确立为 GBM 的一个新的治疗靶点。
