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.
Highlights
Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM)
We extended our prior work by focusing on tumor-initiating cell (TIC) related to the tumor edge, which presumably act as a major source of tumor recurrence (RICs)
Immunohistochemical staining (IHC) demonstrated that edge samples are enriched with Olig2+ cells, while core samples show higher expression of CD109—a putative core marker11. (Supplementary Fig. 1c)
Summary
Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Puchalski et al.[6] subsequently presented the Ivy Glioblastoma Atlas Project (IvyGAP), an anatomical atlas of human GBM that contains mutation and gene expression data obtained from morphologically distinct regions within the tumors In this IvyGAP dataset, different regions of GBM were primarily identified by the histological appearance of the tumor sections, due to the fact that only a limited number of protein markers for GBM spatial heterogeneity have been identified so far. The applicability of these two markers for spatial identity has not been thoroughly validated These aforementioned studies primarily describe GBM heterogeneity within the resectable region of the tumor, while the functional characterization of tumor cells at the infiltrating edge has largely remain elusive. The precise role of intratumoral crosstalk between spatially distinct tumor cells and its underlying mechanisms remain poorly understood
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