Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression

被引：261

作者：

Miroshnikova, Yekaterina A. ^{[1
]}

Mouw, Janna K. ^{[1
]}

Barnes, J. Matthew ^{[1
]}

Pickup, Michael W. ^{[1
]}

Lakins, Johnathan N. ^{[1
]}

Kim, Youngmi ^{[2
,3
]}

Lobo, Khadjia ^{[4
]}

Persson, Anders I. ^{[5
,6
,7
,8
]}

Reis, Gerald F. ^{[9
]}

McKnight, Tracy R. ^{[4
]}

Holland, Eric C. ^{[2
,3
]}

Phillips, Joanna J. ^{[6
,7
,8
,9
]}

Weaver, Valerie M. ^{[1
,10
,11
,12
,13
]}

机构：

[1] Univ Calif San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat, San Francisco, CA 94143 USA

[2] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Human Biol & Solid Tumor Translat Res, Dept Neurosurg, Seattle, WA 98109 USA

[3] Univ Washington, Alvord Brain Tumor Ctr, Seattle, WA 98195 USA

[4] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Magnet Resonance Sci Ctr, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Helen Diller Family Canc Res Ctr, Brain Tumor Res Ctr, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Helen Diller Family Canc Res Ctr, UCSF Comprehens Canc Ctr, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[10] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[11] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[12] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA

[13] Univ Calif San Francisco, UCSF Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 12期

基金：

美国国家卫生研究院;

关键词：

MESENCHYMAL TRANSITION; MALIGNANT GLIOMA; EXPRESSION; HYPOXIA; IDH1; 2-HYDROXYGLUTARATE; INHIBITION; MUTATIONS; PATHWAYS; BIOLOGY;

D O I：

10.1038/ncb3429

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1 alpha. We found that glioma aggression and patient prognosis correlate with HIF1 alpha levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain-and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1 alpha-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1 alpha and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.

引用

页码：1336 / +

页数：19

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