Glioblastoma (GBM) is the most lethal form of brain cancer in adults. The median survival of GBM patients is only about one year after initial diagnosis. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways, including RTK/RAS/PI3K, P53 and RB pathways. Loss of PTEN, TP53 and CDKN2A tumor suppressors, and amplification of EGFR are frequently observed in GBM. However, targeted therapies, such as therapy against EGFR, have failed in the clinic, and no effective therapeutic drugs available to target tumor suppressors. 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 cancer cell 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 (GSEA) and functional validation demonstrated that activation of SRC and AKT signaling pathways drives LOX upregulation in PTEN-deficient cancer cells via the YAP1-TEAD complex. Upon the secretion from PTEN-deficient cancer cells, LOX can be uptaken by macrophages via integrin β1 signaling. Using the phospho-kinase antibody array, we identified PYK2 as the main downstream of LOX that is responsible for macrophage migration. 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. Bioinformatics analysis in clinical samples demonstrated that PTEN-YAP1-LOX-integrin β1 axis is enriched in GBM patients with higher macrophage density, and that these patients show lower survival. Together, our findings highlight the significance of PTEN-YAP1-LOX-integrin β1 axis in macrophage infiltration in GBM, and demonstrate a possibility of improving GBM treatment by targeting this axis-mediated macrophage recruitment.

Citation Format: Peiwen Chen, Alan Y. Wang, Ronald A. DePinho. Lysyl oxidase secreted by PTEN-deficient glioblastoma cells recruits macrophages and promotes malignant growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 117.