Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma

被引：303

作者：

Chen, Peiwen ^{[1
]}

Zhao, Di ^{[1
]}

Li, Jun ^{[2
]}

Liang, Xin ^{[1
,4
]}

Li, Jiexi ^{[1
]}

Chang, Andrew ^{[1
]}

Henry, Verlene K. ^{[3
]}

Lan, Zhengdao ^{[1
,5
]}

Spring, Denise J. ^{[1
]}

Rao, Ganesh ^{[3
]}

Wang, Y. Alan ^{[1
]}

DePinho, Ronald A. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[5] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA

来源：

CANCER CELL | 2019年 / 35卷 / 06期

关键词：

INDUCED LYSYL OXIDASE; GLIOBLASTOMA; EXPRESSION; DIFFERENTIATION; ANGIOGENESIS; POLARIZATION; PROGRESSION; ACTIVATION; INHIBITOR; LANDSCAPE;

D O I：

10.1016/j.ccell.2019.05.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the beta 1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and beta 1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.

引用

页码：868 / +

页数：23

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