Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Soniya Bastola; Marat S. Pavlyukov; Daisuke Yamashita; Sadashib Ghosh; Heejin Cho; Noritaka Kagaya; Zhuo Zhang; Mutsuko Minata; Yeri Lee; Hirokazu Sadahiro; Shinobu Yamaguchi; Svetlana Komarova; Eddy Yang; James Markert; Louis B. Nabors; Krishna Bhat; James Lee; Qin Chen; David K. Crossman; Kazuo Shin-Ya; Do Hyun Nam; Ichiro Nakano

doi:10.1038/s41467-020-18189-y

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Soniya Bastola, Marat S. Pavlyukov, Daisuke Yamashita, Sadashib Ghosh, Heejin Cho, Noritaka Kagaya, Zhuo Zhang, Mutsuko Minata, Yeri Lee, Hirokazu Sadahiro, Shinobu Yamaguchi, Svetlana Komarova, Eddy Yang, James Markert, Louis B. Nabors, Krishna Bhat, James Lee, Qin Chen, David K. Crossman, Kazuo Shin-YaDo Hyun Nam, Ichiro Nakano

Radiation Medicine

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

52 Scopus citations

Abstract

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

Original language	English
Article number	4660
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18189-y
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
We would like to thank members of Dr. Nakano’s lab at the University of Alabama (UAB) at Birmingham for input on manuscript writing and editing. We thank Dr. Harley I. Kornblum (M.D., Ph.D.) at the University of California, Los Angeles for sharing GBM spheres (157, 336, 339, 374, and 408). We would like to thank the UAB High Resolution Imaging facility, Comprehensive Cancer Center bio-imaging core and proteomics core service teams, funded by National Institute of Health (NIH); National Cancer Institute (NCI), project # P30CA013148, and also the UAB Institutional Core Funding Mechanism. MSP was supported by the Russian Foundation for Basic Research grant 20-34-70147 and Russian Science Foundation grant 19-44-02027 (LС-MS/MS analysis and RNA sequencing). I.N. was supported by NIH grants: R01NS083767, R01NS087913, R01CA183991 and R01CA201402. A special thanks to Joseph R. Gould (Department of Microbiology, UAB) for his diligent editing and proofreading of this manuscript.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

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10.1038/s41467-020-18189-y

Cite this

Bastola, S., Pavlyukov, M. S., Yamashita, D., Ghosh, S., Cho, H., Kagaya, N., Zhang, Z., Minata, M., Lee, Y., Sadahiro, H., Yamaguchi, S., Komarova, S., Yang, E., Markert, J., Nabors, L. B., Bhat, K., Lee, J., Chen, Q., Crossman, D. K., ... Nakano, I. (2020). Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy. Nature Communications, 11(1), [4660]. https://doi.org/10.1038/s41467-020-18189-y

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title = "Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy",

abstract = "Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.",

author = "Soniya Bastola and Pavlyukov, {Marat S.} and Daisuke Yamashita and Sadashib Ghosh and Heejin Cho and Noritaka Kagaya and Zhuo Zhang and Mutsuko Minata and Yeri Lee and Hirokazu Sadahiro and Shinobu Yamaguchi and Svetlana Komarova and Eddy Yang and James Markert and Nabors, {Louis B.} and Krishna Bhat and James Lee and Qin Chen and Crossman, {David K.} and Kazuo Shin-Ya and Nam, {Do Hyun} and Ichiro Nakano",

note = "Funding Information: We would like to thank members of Dr. Nakano{\textquoteright}s lab at the University of Alabama (UAB) at Birmingham for input on manuscript writing and editing. We thank Dr. Harley I. Kornblum (M.D., Ph.D.) at the University of California, Los Angeles for sharing GBM spheres (157, 336, 339, 374, and 408). We would like to thank the UAB High Resolution Imaging facility, Comprehensive Cancer Center bio-imaging core and proteomics core service teams, funded by National Institute of Health (NIH); National Cancer Institute (NCI), project # P30CA013148, and also the UAB Institutional Core Funding Mechanism. MSP was supported by the Russian Foundation for Basic Research grant 20-34-70147 and Russian Science Foundation grant 19-44-02027 (LС-MS/MS analysis and RNA sequencing). I.N. was supported by NIH grants: R01NS083767, R01NS087913, R01CA183991 and R01CA201402. A special thanks to Joseph R. Gould (Department of Microbiology, UAB) for his diligent editing and proofreading of this manuscript. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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Bastola, S, Pavlyukov, MS, Yamashita, D, Ghosh, S, Cho, H, Kagaya, N, Zhang, Z, Minata, M, Lee, Y, Sadahiro, H, Yamaguchi, S, Komarova, S, Yang, E, Markert, J, Nabors, LB, Bhat, K, Lee, J, Chen, Q, Crossman, DK, Shin-Ya, K, Nam, DH & Nakano, I 2020, 'Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy', Nature Communications, vol. 11, no. 1, 4660. https://doi.org/10.1038/s41467-020-18189-y

TY - JOUR

T1 - Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

AU - Bastola, Soniya

AU - Pavlyukov, Marat S.

AU - Yamashita, Daisuke

AU - Ghosh, Sadashib

AU - Cho, Heejin

AU - Kagaya, Noritaka

AU - Zhang, Zhuo

AU - Minata, Mutsuko

AU - Lee, Yeri

AU - Sadahiro, Hirokazu

AU - Yamaguchi, Shinobu

AU - Komarova, Svetlana

AU - Yang, Eddy

AU - Markert, James

AU - Nabors, Louis B.

AU - Bhat, Krishna

AU - Lee, James

AU - Chen, Qin

AU - Crossman, David K.

AU - Shin-Ya, Kazuo

AU - Nam, Do Hyun

AU - Nakano, Ichiro

N1 - Funding Information: We would like to thank members of Dr. Nakano’s lab at the University of Alabama (UAB) at Birmingham for input on manuscript writing and editing. We thank Dr. Harley I. Kornblum (M.D., Ph.D.) at the University of California, Los Angeles for sharing GBM spheres (157, 336, 339, 374, and 408). We would like to thank the UAB High Resolution Imaging facility, Comprehensive Cancer Center bio-imaging core and proteomics core service teams, funded by National Institute of Health (NIH); National Cancer Institute (NCI), project # P30CA013148, and also the UAB Institutional Core Funding Mechanism. MSP was supported by the Russian Foundation for Basic Research grant 20-34-70147 and Russian Science Foundation grant 19-44-02027 (LС-MS/MS analysis and RNA sequencing). I.N. was supported by NIH grants: R01NS083767, R01NS087913, R01CA183991 and R01CA201402. A special thanks to Joseph R. Gould (Department of Microbiology, UAB) for his diligent editing and proofreading of this manuscript. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

AB - Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

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Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Abstract

Bibliographical note

ASJC Scopus subject areas

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