Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma

Tanwir Hasan; Seamus P. Caragher; Jack M. Shireman; Cheol H. Park; Fatemeh Atashi; Shivani Baisiwala; Gina Lee; Donna Guo; Jennifer Y. Wang; Mahua Dey; Meijing Wu; Maciej S. Lesniak; Craig M. Horbinski; C. David James; Atique U. Ahmed

doi:10.1038/s41419-019-1387-6

Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma

Tanwir Hasan, Seamus P. Caragher, Jack M. Shireman, Cheol H. Park, Fatemeh Atashi, Shivani Baisiwala, Gina Lee, Donna Guo, Jennifer Y. Wang, Mahua Dey, Meijing Wu, Maciej S. Lesniak, Craig M. Horbinski, C. David James, Atique U. Ahmed^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

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.

Original language	English (US)
Article number	292
Journal	Cell Death and Disease
Volume	10
Issue number	4
DOIs	https://doi.org/10.1038/s41419-019-1387-6
State	Published - Apr 1 2019

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS096376, the American Cancer Society grant RSG-16–034–01-DDC (to A.U.A.) grant, National Cancer Institute grant R35CA197725 (to M.S.L.), P50CA221747 SPORE for Translational Approaches to Brain Cancer and R01NS095642 (to C.D.J). We would like to thank Ting Xiao for the statistical analysis for the preparation of this paper.

ASJC Scopus subject areas

Cellular and Molecular Neuroscience
Cancer Research
Cell Biology
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41419-019-1387-6

Cite this

Hasan, T., Caragher, S. P., Shireman, J. M., Park, C. H., Atashi, F., Baisiwala, S., Lee, G., Guo, D., Wang, J. Y., Dey, M., Wu, M., Lesniak, M. S., Horbinski, C. M., James, C. D., & Ahmed, A. U. (2019). Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death and Disease, 10(4), Article 292. https://doi.org/10.1038/s41419-019-1387-6

@article{e69475dcad274aabbaf9ccfbf8acd3cf,

title = "Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma",

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.",

author = "Tanwir Hasan and Caragher, {Seamus P.} and Shireman, {Jack M.} and Park, {Cheol H.} and Fatemeh Atashi and Shivani Baisiwala and Gina Lee and Donna Guo and Wang, {Jennifer Y.} and Mahua Dey and Meijing Wu and Lesniak, {Maciej S.} and Horbinski, {Craig M.} and James, {C. David} and Ahmed, {Atique U.}",

note = "Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS096376, the American Cancer Society grant RSG-16–034–01-DDC (to A.U.A.) grant, National Cancer Institute grant R35CA197725 (to M.S.L.), P50CA221747 SPORE for Translational Approaches to Brain Cancer and R01NS095642 (to C.D.J). We would like to thank Ting Xiao for the statistical analysis for the preparation of this paper. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = apr,

day = "1",

doi = "10.1038/s41419-019-1387-6",

language = "English (US)",

volume = "10",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Springer Nature",

number = "4",

}

Hasan, T, Caragher, SP, Shireman, JM, Park, CH, Atashi, F, Baisiwala, S, Lee, G, Guo, D, Wang, JY, Dey, M, Wu, M, Lesniak, MS , Horbinski, CM , James, CD & Ahmed, AU 2019, 'Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma', Cell Death and Disease, vol. 10, no. 4, 292. https://doi.org/10.1038/s41419-019-1387-6

TY - JOUR

T1 - Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma

AU - Hasan, Tanwir

AU - Caragher, Seamus P.

AU - Shireman, Jack M.

AU - Park, Cheol H.

AU - Atashi, Fatemeh

AU - Baisiwala, Shivani

AU - Lee, Gina

AU - Guo, Donna

AU - Wang, Jennifer Y.

AU - Dey, Mahua

AU - Wu, Meijing

AU - Lesniak, Maciej S.

AU - Horbinski, Craig M.

AU - James, C. David

AU - Ahmed, Atique U.

N1 - Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS096376, the American Cancer Society grant RSG-16–034–01-DDC (to A.U.A.) grant, National Cancer Institute grant R35CA197725 (to M.S.L.), P50CA221747 SPORE for Translational Approaches to Brain Cancer and R01NS095642 (to C.D.J). We would like to thank Ting Xiao for the statistical analysis for the preparation of this paper. Publisher Copyright: © 2019, The Author(s).

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063770179&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063770179&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-1387-6

DO - 10.1038/s41419-019-1387-6

M3 - Article

C2 - 30926789

AN - SCOPUS:85063770179

SN - 2041-4889

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 4

M1 - 292

ER -

Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this