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

Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): 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. DePinhoSummaryHeterotypic 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research