Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells.
Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells.
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DOI：
10.1038/s41591-018-0086-7
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发表时间：
2018-08
期刊：
影响因子：
82.9
通讯作者：
Jones C
中科院分区：
文献类型：
--
作者：
Vinci M;Burford A;Molinari V;Kessler K;Popov S;Clarke M;Taylor KR;Pemberton HN;Lord CJ;Gutteridge A;Forshew T;Carvalho D;Marshall LV;Qin EY;Ingram WJ;Moore AS;Ng HK;Trabelsi S;H'mida-Ben Brahim D;Entz-Werle N;Zacharoulis S;Vaidya S;Mandeville HC;Bridges LR;Martin AJ;Al-Sarraj S;Chandler C;Sunol M;Mora J;de Torres C;Cruz O;Carcaboso AM;Monje M;Mackay A;Jones C
儿科胶质母细胞瘤（pGBM）和弥漫性脑桥胶质瘤（DIPG）的有效治疗方法的开发失败部分是由于它们内在的异质性。我们的目标是通过亚克隆基因组分析来定量地评估这种情况在这些肿瘤中存在的程度，并确定不同的肿瘤亚群是否可以通过在体外和体内产生新的亚克隆患者衍生模型来相互作用以促进肿瘤发生。对142例测序病例的分析显示，多种采样策略观察到多个肿瘤亚克隆在空间和时间上以稳定的方式共存。我们分离了基因型和表型不同的亚群，我们建议合作提高致瘤性和对治疗的抵抗力。H4K20组蛋白甲基转移酶KMT5B （SUV420H1）失活突变存在于<1%的细胞中，通过趋化因子信号传导和整合素的调节，在体外和体内赋予了DNA修复途径的取消和邻近细胞的入侵/迁移增加。这些数据表明，即使是罕见的肿瘤亚群也可能对整个肿瘤的发生产生深远的影响，并可能代表着治疗发展的新途径。揭示pGBM/DIPG亚克隆多样性和交流机制将是克服有效治疗障碍的重要一步。
The failure to develop effective therapies for paediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively map assess the extent to which this was present in these tumours through subclonal genomic analyses, and to determine whether distinct tumour subpopulations may interact to promote tumorigenesis by generating novel subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced cases revealed multiple tumour subclones, spatially and temporally co-existing in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations which we propose co-operate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, confer an abrogated DNA repair pathway and increased invasion/migration of neighbouring cells, in vitro and in vivo, through chemokine signalling and modulation of integrins. These data indicate that even rare tumour subpopulations may exert profound effects on tumorigenesis as a whole, and may represent a novel avenue for therapeutic development. Unravelling the mechanisms of subclonal diversity and communication in pGBM/DIPG will be an important step to overcoming barriers to effective treatments.
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影响因子：
64.8
作者：
Marusyk, Andriy;Tabassum, Doris P.;Altrock, Philipp M.;Almendro, Vanessa;Michor, Franziska;Polyak, Kornelia
通讯作者：
Polyak, Kornelia
DOI：
10.1126/science.1253462
发表时间：
2014-10-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Bruin EC;McGranahan N;Mitter R;Salm M;Wedge DC;Yates L;Jamal-Hanjani M;Shafi S;Murugaesu N;Rowan AJ;Grönroos E;Muhammad MA;Horswell S;Gerlinger M;Varela I;Jones D;Marshall J;Voet T;Van Loo P;Rassl DM;Rintoul RC;Janes SM;Lee SM;Forster M;Ahmad T;Lawrence D;Falzon M;Capitanio A;Harkins TT;Lee CC;Tom W;Teefe E;Chen SC;Begum S;Rabinowitz A;Phillimore B;Spencer-Dene B;Stamp G;Szallasi Z;Matthews N;Stewart A;Campbell P;Swanton C
通讯作者：
Swanton C
影响因子：
82.9
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
通讯作者：
Maley CC
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/btt622
发表时间：
2014-01-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Andor N;Harness JV;Müller S;Mewes HW;Petritsch C
通讯作者：
Petritsch C