Abstract
Glioblastoma (GBM) is the most lethal form of brain cancer in adults with no effective therapeutics. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways, including RTK/RAS/PI-3K, P53 and RB pathways. The main reason for this failure is tumor-cell genetic heterogeneity, which induces aberrant activation of multiple signaling pathways. Stromal/immune cells in the tumor microenvironment (TME) are genetically stable, which not only play a pivotal role in GBM progression by affecting multiple cancer hallmarks, but can also be educated by cancer cells. However, whether and how the behavior and function of specific stromal/immune cells in the TME are regulated by genetic alternations in GBM remain relatively undefined. Here, we show that PTEN deficiency in GBM specifically triggers immune response by promoting macrophage recruitment, while without affecting macroglia and other immune cells. Using unbiased transcriptome profiling, we identified that lysyl oxidase (LOX) is preferentially secreted by PTEN-deficient cancer cells, and is a potent macrophage chemoattractant. Transcriptome profiling following Gene Set Enrichment Analysis and functional validation demonstrated that activation of SRC and AKT signaling pathways drives LOX upregulation in PTEN-deficient cancer cells, thus promoting macrophage recruitment. Following internalization into macrophages mediated by integrin b1, LOX promotes macrophage migration via a newly identified signaling pathway through phosphoprotein profiling. Genetic and pharmacological inhibition of LOX in PTEN-deficient cancer cells does not affect tumor cell proliferation in vitro, but markedly inhibits macrophage density and tumor growth in vivo. Clinically, LOX expression positively correlates with integrin b1, as well as macrophage signature and poor prognosis in GBM patients. LOX-integrin b1 axis is enriched in GBM patients with higher macrophage density, and that these patients show lower survival. Together, our study highlights the possibility of improving GBM treatment by targeting PTEN-LOX axis-mediated macrophage recruitment.