PMID- 31185211 OWN - NLM STAT- MEDLINE DCOM- 20200323 LR - 20220129 IS - 1878-3686 (Electronic) IS - 1535-6108 (Print) IS - 1535-6108 (Linking) VI - 35 IP - 6 DP - 2019 Jun 10 TI - Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma. PG - 868-884.e6 LID - S1535-6108(19)30241-7 [pii] LID - 10.1016/j.ccell.2019.05.003 [doi] AB - 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 beta1 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 beta1 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. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Chen, Peiwen AU - Chen P AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Zhao, Di AU - Zhao D AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Li, Jun AU - Li J AD - Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Liang, Xin AU - Liang X AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Li, Jiexi AU - Li J AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Chang, Andrew AU - Chang A AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Henry, Verlene K AU - Henry VK AD - Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Lan, Zhengdao AU - Lan Z AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Spring, Denise J AU - Spring DJ AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Rao, Ganesh AU - Rao G AD - Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Wang, Y Alan AU - Wang YA AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org. FAU - DePinho, Ronald A AU - DePinho RA AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P01 CA117969/CA/NCI NIH HHS/United States GR - CRI2458/CRI/Cancer Research Institute/United States GR - K99 CA226360/CA/NCI NIH HHS/United States GR - R01 NS094615/NS/NINDS NIH HHS/United States GR - 8808.0/CRI/Cancer Research Institute/United States GR - R01 CA231349/CA/NCI NIH HHS/United States GR - R01 CA084628/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Cell JT - Cancer cell JID - 101130617 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Enzyme Inhibitors) RN - 0 (Integrin beta1) RN - 0 (SPP1 protein, human) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 106441-73-0 (Osteopontin) RN - EC 1.4.3.13 (LOX protein, human) RN - EC 1.4.3.13 (Protein-Lysine 6-Oxidase) RN - EC 2.7.10.2 (Focal Adhesion Kinase 2) RN - EC 2.7.10.2 (PTK2B protein, human) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/metabolism MH - Animals MH - Antineoplastic Agents/pharmacology MH - Biomarkers, Tumor/deficiency/*genetics MH - Brain Neoplasms/drug therapy/enzymology/*genetics/pathology MH - Cell Movement MH - Cell Proliferation MH - Enzyme Inhibitors/pharmacology MH - Female MH - Focal Adhesion Kinase 2/genetics/metabolism MH - Gene Expression Regulation, Neoplastic MH - Glioma/drug therapy/enzymology/*genetics/pathology MH - HEK293 Cells MH - Humans MH - Integrin beta1/genetics/metabolism MH - Macrophages/drug effects/*enzymology/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred ICR MH - Mice, SCID MH - Osteopontin/genetics/metabolism MH - PTEN Phosphohydrolase/deficiency/*genetics MH - *Paracrine Communication/drug effects MH - Protein-Lysine 6-Oxidase/antagonists & inhibitors/genetics/*metabolism MH - RAW 264.7 Cells MH - Signal Transduction MH - *Synthetic Lethal Mutations MH - THP-1 Cells MH - Transcription Factors/genetics/metabolism MH - Tumor Burden MH - Xenograft Model Antitumor Assays MH - YAP-Signaling Proteins PMC - PMC6561349 MID - NIHMS1529766 OTO - NOTNLM OT - PTEN OT - PYK2 OT - SPP1 and YAP1 OT - glioblastoma OT - lysyl oxidase OT - macrophages OT - recruitment COIS- DECLARATION OF INTERESTS RAD is a co-founder, advisor and director of Tvardi Therapeutics. EDAT- 2019/06/12 06:00 MHDA- 2020/03/24 06:00 PMCR- 2020/06/10 CRDT- 2019/06/12 06:00 PHST- 2018/11/07 00:00 [received] PHST- 2019/04/09 00:00 [revised] PHST- 2019/05/09 00:00 [accepted] PHST- 2019/06/12 06:00 [entrez] PHST- 2019/06/12 06:00 [pubmed] PHST- 2020/03/24 06:00 [medline] PHST- 2020/06/10 00:00 [pmc-release] AID - S1535-6108(19)30241-7 [pii] AID - 10.1016/j.ccell.2019.05.003 [doi] PST - ppublish SO - Cancer Cell. 2019 Jun 10;35(6):868-884.e6. doi: 10.1016/j.ccell.2019.05.003.