Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition

被引：170

作者：

Segerman, Anna ^{[1
,3
]}

Niklasson, Mia ^{[1
]}

Haglund, Caroline ^{[2
]}

Bergstrom, Tobias ^{[1
]}

Jarvius, Malin ^{[2
]}

Xie, Yuan ^{[1
]}

Westermark, Ann ^{[1
]}

Sonmez, Demet ^{[1
,6
]}

Hermansson, Annika ^{[1
]}

Kastemar, Marianne ^{[1
]}

Naimaie-Ali, Zeinab ^{[1
]}

Nyberg, Frida ^{[2
]}

Berglund, Malin ^{[2
]}

Sundstrom, Magnus ^{[1
]}

Hesselager, Goran ^{[4
]}

Uhrbom, Lene ^{[1
]}

Gustafsson, Mats ^{[2
]}

Larsson, Rolf ^{[2
]}

Fryknas, Marten ^{[2
]}

Segerman, Bo ^{[1
,5
]}

Westermark, Bengt ^{[1
]}

机构：

[1] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, S-75185 Uppsala, Sweden

[2] Uppsala Univ, Univ Uppsala Hosp, Dept Med Sci, Canc Pharmacol & Computat Med, S-75185 Uppsala, Sweden

[3] Univ Uppsala Hosp, Clin Chem & Pharmacol, S-75185 Uppsala, Sweden

[4] Univ Uppsala Hosp, Dept Neurosurg, S-75185 Uppsala, Sweden

[5] Natl Vet Inst, S-75007 Uppsala, Sweden

[6] Pfizer, Vetenskapsvagen 10, S-19190 Sollentuna, Sweden

来源：

CELL REPORTS | 2016年 / 17卷 / 11期

关键词：

CANCER STEM-CELLS; BRAIN-TUMORS; INTRATUMORAL HETEROGENEITY; GENE-EXPRESSION; IN-VIVO; GLIOBLASTOMA; METHYLATION; RESISTANCE; SUBTYPES; EGFR;

D O I：

10.1016/j.celrep.2016.11.056

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

引用

页码：2994 / 3009

页数：16

共 2 条

[1] In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift
Halliday, John
Helmy, Karim
Pattwell, Siobhan S.
Pitter, Kenneth L.
LaPlant, Quincey
Ozawa, Tatsuya
Holland, Eric C.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (14) : 5248 - 5253
[2] Macrophage Membrane-Coated Nanoparticles Sensitize Glioblastoma to Radiation by Suppressing Proneural-Mesenchymal Transformation in Glioma Stem Cells
Li, Ruiqi
Chen, Lian
Ji, Qin
Liang, Qing
Zhu, Ying
Fu, Wei
Chen, Tianyou
Duan, Hongwei
He, Wenshan
Xu, Zushun
Dai, Xiaofang
Ren, Jinghua
ADVANCED FUNCTIONAL MATERIALS, 2023, 33 (37)

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