@article{2943e7810d1b4db8847985def075302f,
title = "Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma",
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. Chen et al. find that PTEN deficiency in glioblastoma (GBM) increases macrophage infiltration via a YAP1-LOX-β1 integrin-PYK2 axis, the infiltrated macrophages in turn secrete SPP1 to support GBM survival. In PTEN-null GBM xenograft mouse models, inhibition of LOX reduces macrophage infiltration and tumor growth.",
keywords = "PTEN, PYK2, SPP1 and YAP1, glioblastoma, lysyl oxidase, macrophages, recruitment",
author = "Peiwen Chen and Di Zhao and Jun Li and Xin Liang and Jiexi Li and Andrew Chang and Henry, {Verlene K.} and Zhengdao Lan and Spring, {Denise J.} and Ganesh Rao and Wang, {Y. Alan} and DePinho, {Ronald A.}",
note = "Funding Information: We thank Peoples MD for providing shRNAs, F.F. Lang, W.J.A.J. Hendriks, S.D. Rabkin, J. Hu, R.M. Bachoo, and E. Tasciotti for providing cell lines; B. Hu for providing P53DN-AKT-hNSC tumor sections; C.V. Kingsley and V. Tran for assistance with imaging; and S. Jiang for mouse husbandry. This work was supported in part by the Cancer Research Institute Irvington Postdoctoral Fellowship (to P.C.), the Caroline Ross Endowed Fellowship (to P.C.), The Harold C. and Mary L. Daily Endowment Fellowship (to P.C.), the Burkhart III Distinguished University Chair in Cancer Research Endowment (to R.A.D.), Clayton & Modesta William Cancer Research Fund (to R.A.D.), NIH P01 CA117969 (to R.A.D.), NIH R01 CA084628 (to R.A.D.), Emerson Collective Award (to Y.A.W.), NIH R01 CA231349 (to Y.A.W.), NIH K99 CA226360 (to D.Z.), and NIH R01 NS094615 (to G.R.). The core facilities at MD Anderson are supported by P30CA16672 . Funding Information: We thank Peoples MD for providing shRNAs, F.F. Lang, W.J.A.J. Hendriks, S.D. Rabkin, J. Hu, R.M. Bachoo, and E. Tasciotti for providing cell lines; B. Hu for providing P53DN-AKT-hNSC tumor sections; C.V. Kingsley and V. Tran for assistance with imaging; and S. Jiang for mouse husbandry. This work was supported in part by the Cancer Research Institute Irvington Postdoctoral Fellowship (to P.C.), the Caroline Ross Endowed Fellowship (to P.C.), The Harold C. and Mary L. Daily Endowment Fellowship (to P.C.), the Burkhart III Distinguished University Chair in Cancer Research Endowment (to R.A.D.), Clayton & Modesta William Cancer Research Fund (to R.A.D.), NIH P01 CA117969 (to R.A.D.), NIH R01 CA084628 (to R.A.D.), Emerson Collective Award (to Y.A.W.), NIH R01 CA231349 (to Y.A.W.), NIH K99 CA226360 (to D.Z.), and NIH R01 NS094615 (to G.R.). The core facilities at MD Anderson are supported by P30CA16672. P.C. R.A.D. and Y.A.W. designed the project. P.C. performed most of the experiments. D.Z. provided assistance for performing microarray and CRISPR-KO. J.L. provided assistance for TCGA data analysis. X.L. and A.C. provided assistance for immunostaining. J.L. and Z.L. provided assistance for ChIP experiments. V.K.H. and G.R. helped to generate GBM mouse models. P.C. R.A.D. and Y.A.W. wrote the manuscript. D.J.S. edited the paper. R.A.D. is a co-founder, advisor and director of Tvardi Therapeutics. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jun,
day = "10",
doi = "10.1016/j.ccell.2019.05.003",
language = "English (US)",
volume = "35",
pages = "868--884.e6",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}