Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma
dc.contributor.author | Hasan, Tanwir | |
dc.contributor.author | Caragher, Seamus P. | |
dc.contributor.author | Shireman, Jack M. | |
dc.contributor.author | Park, Cheol H. | |
dc.contributor.author | Atashi, Fatemeh | |
dc.contributor.author | Baisiwala, Shivani | |
dc.contributor.author | Lee, Gina | |
dc.contributor.author | Guo, Donna | |
dc.contributor.author | Wang, Jennifer Y. | |
dc.contributor.author | Dey, Mahua | |
dc.contributor.author | Wu, Meijing | |
dc.contributor.author | Lesniak, Maciej S. | |
dc.contributor.author | Horbinski, Craig M. | |
dc.contributor.author | James, C. David | |
dc.contributor.author | Ahmed, Atique U. | |
dc.contributor.department | Neurological Surgery, School of Medicine | en_US |
dc.date.accessioned | 2019-08-02T16:26:39Z | |
dc.date.available | 2019-08-02T16:26:39Z | |
dc.date.issued | 2019-03-29 | |
dc.description.abstract | 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. | en_US |
dc.identifier.citation | Hasan, T., Caragher, S. P., Shireman, J. M., Park, C. H., Atashi, F., Baisiwala, S., … Ahmed, A. U. (2019). Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell death & disease, 10(4), 292. doi:10.1038/s41419-019-1387-6 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/20161 | |
dc.language.iso | en_US | en_US |
dc.publisher | Springer Nature | en_US |
dc.relation.isversionof | 10.1038/s41419-019-1387-6 | en_US |
dc.relation.journal | Cell Death & Disease | en_US |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | * |
dc.source | PMC | en_US |
dc.subject | Glioma-initiating cells (GICs) | en_US |
dc.subject | Therapy-induced cellular plasticity | en_US |
dc.subject | Cancer Genome Atlas | en_US |
dc.subject | Ivy Glioblastoma Atlas Project | en_US |
dc.title | Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma | en_US |
dc.type | Article | en_US |