A Novel, Diffusely Infiltrative Xenograft Model of Human Anaplastic Oligodendroglioma with Mutations in FUBP1, CIC, and IDH1

Abstract

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

“…Despite their frequent occurrence, glioma xenografts carrying these mutations are very scarce (41,52,53), and in vitro propagation of IDH1-mutated glioma cell lines is challenging (54). Interestingly, and in line with clinical observations, E478 xenografts present with lower proliferation rates than IDHwt counterparts, as established via the Ki67 index, and mice carrying these xenografts have a longer survival time than mice carrying IDHwt xenografts (see Supplementary Materials).…”

BMP Signaling Induces Astrocytic Differentiation of Clinically Derived Oligodendroglioma Propagating Cells

“…Substantially higher amounts of cellular debris were present in these cultures, and multiple media changes were required before spheres were readily detectable. These differences in sphere-forming latency and debris quantity may have led previous groups to prematurely conclude that their culture attempts were unsuccessful (11, 22). Of note, many of the cells that adhered to the flask and failed to form spheres demonstrated small dark nuclei and abundant cytoplasm similar to immature oligodendrocytic cells early in culture (Figure 1A, inset).…”

“…Kelly et al reported sphere-forming capacity and multipotent differentiation (7), similar to our findings, suggesting that OligPCs exhibit properties of neural stem cells and GSCs isolated from astrocytomas. Other groups, however, have observed deficiencies in the ability of OligPCs to form spheres (22), and reported a more restricted capacity for differentiation (11). These findings, combined with their observation that OligPC tumorigenicity is enriched in NG2-positive cells but not CD133-positive cells, led Persson et al to conclude that OligPCs are more closely related to oligodendrocyte precursor cells rather than neural stem cells.…”

Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

“…Successful propagation of tumor initiating cells (TICs), cancer cells that display stem cell properties, and generation of intracerebral glioma xenografts from IDH -mutant patient gliomas are rare (22-25). The reasons for the difficulty in establishing models from patient IDH -mutant gliomas are unknown.…”