Browsing by Author "Horbinski, Craig M."

Now showing 1 - 3 of 3
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    CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells
    (AACR Publications, 2016-10-01) Chang, Alan L.; Miska, Jason; Wainwright, Derek A.; Dey, Mahua; Rivetta, Claudia V.; Yu, Dou; Kanojia, Deepak; Pituch, Katarzyna C.; Qiao, Jian; Pytel, Peter; Han, Yu; Wu, Meijing; Zhang, Lingjiao; Horbinski, Craig M.; Ahmed, Atique U.; Lesniak, Maciej S.; Neurological Surgery, School of Medicine
    In many aggressive cancers, such as glioblastoma multiforme (GBM), progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). However, the mechanistic details of how Treg and MDSC are recruited in various tumors is not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSC in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Treg and monocytic MDSC. In mixed-bone marrow chimera assays, we found that CCR4-deficient Treg and CCR2-deficient monocytic MDSC were defective in glioma accumulation. Further, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of GBM, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Lastly, we found that CD163-positive infiltrating macrophages were a major source of CCL2 in GBM patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.
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    Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma
    (Springer Nature, 2019-03-29) Hasan, Tanwir; Caragher, Seamus P.; Shireman, Jack M.; Park, Cheol H.; Atashi, Fatemeh; Baisiwala, Shivani; Lee, Gina; Guo, Donna; Wang, Jennifer Y.; Dey, Mahua; Wu, Meijing; Lesniak, Maciej S.; Horbinski, Craig M.; James, C. David; Ahmed, Atique U.; Neurological Surgery, School of Medicine
    Emerging evidence reveals enrichment of glioma-initiating cells (GICs) following therapeutic intervention. One factor known to contribute to this enrichment is cellular plasticity-the ability of glioma cells to attain multiple phenotypes. To elucidate the molecular mechanisms governing therapy-induced cellular plasticity, we performed genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression analysis (gene microarray analysis) during treatment with standard of care temozolomide (TMZ) chemotherapy. Analysis revealed significant enhancement of open-chromatin marks in known astrocytic enhancers for interleukin-8 (IL-8) loci as well as elevated expression during anti-glioma chemotherapy. The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence. Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold, p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27. Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence.
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    MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma
    (Elsevier, 2017-12-11) Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A.; Pangeni, Rajendra P.; Wan, Xuechao; Song, Xiao; Shi, Taiping; Yang, Yongyong; Sastry, Namratha; Horbinski, Craig M.; Lu, Songjian; Stupp, Roger; Kessler, John A.; Nishikawa, Ryo; Nakano, Ichiro; Sulman, Erik P.; Lu, Xinghua; James, Charles David; Yin, Xiao-Ming; Hu, Bo; Cheng, Shi-Yuan; Pathology and Laboratory Medicine, School of Medicine
    ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy., • MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells • MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383 • Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy • Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models , Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.