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.
|State||Published - Dec 1 2020|
Bibliographical noteFunding 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.
© 2020, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)