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Cancer Cell. 2019 Jun 10;35(6):868-884.e6. doi: 10.1016/j.ccell.2019.05.003.

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

Author information

1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org.
5
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.

Abstract

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 β1 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 β1 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.

KEYWORDS:

PTEN; PYK2; SPP1 and YAP1; glioblastoma; lysyl oxidase; macrophages; recruitment

PMID:
31185211
PMCID:
PMC6561349
[Available on 2020-06-10]
DOI:
10.1016/j.ccell.2019.05.003

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