Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma.
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma.
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DOI：
10.1038/s41419-021-03657-0
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发表时间：
2021-04-07
影响因子：
9
通讯作者：
Nam DH
中科院分区：
文献类型：
--
作者：
Choi SW;Lee Y;Shin K;Koo H;Kim D;Sa JK;Cho HJ;Shin HM;Lee SJ;Kim H;Chung S;Shin J;Lee C;Nam DH
PTEN是恶性肿瘤中最常发生变化的抑癌基因之一。PTEN突变的显性负效应提示，PTEN突变的功能异常可能比缺失更具灾难性，而缺失是胶质母细胞瘤中最常见的基因组事件。本研究旨在了解各种PTEN错义突变的功能特性，并探讨它们的临床相关性。使用三星医疗中心GBM队列分析PTEN改变的基因组图谱，并通过癌症基因组图谱数据集进行验证。确定了几个热点突变，并对它们的亚细胞分布和表型进行了评估。我们使用U87 MG和缺乏功能性PTEN的患者来源的细胞模型建立了过表达这些突变蛋白的癌细胞系的文库。PTEN突变主要分为两个亚组：磷酸酶结构域的错义突变和C2结构域的主干突变。我们测定了前一组的四个突变蛋白(H93Y、C124S、R130Q和R173C)的亚细胞区划，发现它们有不同的定位；与侵袭性表型(‘边缘突变’)相关的蛋白定位于细胞外围，而R173C突变定位于细胞核。边缘置换产生的侵袭性表型不受抗PI3K/Akt试剂的影响，但可被微管抑制剂破坏。PTEN突变在其亚细胞定位方面表现出不同的功能特性。此外，磷酸酶结构域中的一些错义突变(边缘突变)导致与细胞骨架组装功能障碍相关的侵袭性增加，因此表明它是一个有效的治疗靶点。
PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.
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影响因子：
4.2
作者：
Burger, Matthew T.;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.
影响因子：
4
作者：
Planchon, Sarah M.;Waite, Kristin A.;Eng, Charis
通讯作者：
Eng, Charis
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.
DOI：
10.1158/1078-0432.ccr-11-1558
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Koul D;Fu J;Shen R;LaFortune TA;Wang S;Tiao N;Kim YW;Liu JL;Ramnarian D;Yuan Y;Garcia-Echevrria C;Maira SM;Yung WK
通讯作者：
Yung WK
影响因子：
4.6
作者：
de Gooijer MC;Zhang P;Buil LCM;Çitirikkaya CH;Thota N;Beijnen JH;van Tellingen O
通讯作者：
van Tellingen O