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.

Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism

“…All 37 longitudinal glioblastoma cases were treated at Samsung Medical Center and Seoul National University Hospital and the tumor tissues were collected for research under the approved institutional review boards. Detailed methods are described in the previous study 16 and Supplementary Material . For the preclinical studies, 4 patient-derived glioma sphere models were used, including 3 pair of tumor core- and edge-derived ones (1051E and C, 1053E and C, and 0573E and C) as well as one tumor edge-derived sphere line (101027E), which were established and described elsewhere.…”

“…For the preclinical studies, 4 patient-derived glioma sphere models were used, including 3 pair of tumor core- and edge-derived ones (1051E and C, 1053E and C, and 0573E and C) as well as one tumor edge-derived sphere line (101027E), which were established and described elsewhere. 3 , 16 , 18–22 In short, with the signed patient consent, the senior author (I.N.) performed supra-total resection of glioblastoma tumors under the awake setting and resected both tumor core (T1-Gadolinium(+) tumors) and edge (T1-Gadolinium(-)/T2-FLAIR abnormal tumors in the noneloquent deep white matter) to achieve maximal tumor cell eradication without causing any permanent major deficits in the patients ( Supplementary Figure 1A ).…”

“…After the confirmation of enough tumor tissues from both lesions secured for the clinical diagnosis, remaining tissues were provided to the corresponding scientists following de-identification of the patient information. Both the core-derived and edge-derived glioma spheres were established in the same culture condition 3 , 16 , 18–24 and their spatial identities, termed core-ness and edge-ness , were confirmed by a set of xenografting experiments into mouse brains (details described in ref. 16 ).…”

“…Molecular and, more importantly, phenotypic characterization of these edge-TICs may lead to the identification of a means to inhibit the process of tumor recurrence after failure of the current therapies for glioblastoma. 16 , 17…”

“…This has allowed us to functional identify CD133 and CD109 as the representative molecules of the edge -located and acquired core -associated TICs, respectively. 3 , 16 , 18 , 19 …”