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.

• Authors: Peiwen Chen, Di Zhao, Jun Li, Xin Liang, Jiexi Li, Andrew Chang, Verlene K Henry, Zhengdao Lan, Denise J Spring, Ganesh Rao, Y Alan Wang, Ronald A DePinho
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 6 Pg. 868-884.e6 (06 10 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31185211 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Biomarkers, Tumor
• Enzyme Inhibitors
• Integrin beta1
• SPP1 protein, human
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Osteopontin
• LOX protein, human
• Protein-Lysine 6-Oxidase
• Focal Adhesion Kinase 2
• PTK2B protein, human
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (deficiency, genetics)
• Brain Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Movement
• Cell Proliferation
• Enzyme Inhibitors (pharmacology)
• Female
• Focal Adhesion Kinase 2 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Glioma (drug therapy, enzymology, genetics, pathology)
• HEK293 Cells
• Humans
• Integrin beta1 (genetics, metabolism)
• Macrophages (drug effects, enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, SCID
• Osteopontin (genetics, metabolism)
• PTEN Phosphohydrolase (deficiency, genetics)
• Paracrine Communication (drug effects)
• Protein-Lysine 6-Oxidase (antagonists & inhibitors, genetics, metabolism)
• RAW 264.7 Cells
• Signal Transduction
• Synthetic Lethal Mutations
• THP-1 Cells
• Transcription Factors (genetics, metabolism)
• Tumor Burden
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins