Mouse Models of Pediatric Supratentorial High-grade Glioma Reveal How Cell-of-Origin Influences Tumor Development and Phenotype

Abstract

High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease. Cancer Res; 77(3); 802-12. ©2016 AACR.

Anatomic mapping of molecular subtypes in diffuse glioma

“…In order to verify our hypothesis, we tried to study the interconnection between anatomic location and genetic biomarkers in our patient cohort. Beforehand, many papers published have put forward the cell origin theory underlying possible relationship between these two factors [ 20 , 21 ]. Many groups have successfully developed computational methods to predict glioma genetic alterations based on location features [ 18 , 22 , 23 ].…”

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

“…All GSC cultures were derived from anonymized grade IV, nonrecurrent glioblastoma samples obtained from patients undergoing surgical resection at Uppsala University Hospital in accordance with protocols approved by the regional ethical review board (2007/353) and following patients' written consent . Sixty IDH1 wild‐type cultures were used at passages 5–15 and were tested negative for mycoplasma using two different methods, MycoAlert Mycoplasma Detection kit (Lonza, Basel, Switzerland) and a PCR‐based method as previously described . For details, see supplementary materials, Supplementary materials and methods.…”

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

“…We know from previous studies in the lab using mouse models of GBM that the developmental state of the cell of origin can influence both the molecular subtype of the developed tumor and its ability to establish a SF culture (Jiang et al, ; Sreedharan et al, ). We have found that a more differentiated glial origin produced GBM cells that were difficult to maintain in culture compared to a neural stem cell‐like origin (Sreedharan et al, ). Differences in maintainability due to cell of origin has also been reported by others (Ledur et al, ).…”