Abstract 3907: Invasive properties of GSCs with known IDH1 status into human cerebral organoids

Abstract

Abstract Glioblastomas (GBM) are malignant Grade IV tumors whose prognosis for patients remains dismal, with median survival of 14.6 months after the standard therapy. GBMs have a high proliferative index and are highly invasive to normal brain tissue. GBMs characteristically exhibit areas of necrosis and recruitment of abnormal blood vessels. The most common form of GBMs are primary GBMs (~95%), with no prior clinical history and have poor clinical outcome. Secondary GBMs arise from lower-grade gliomas and are associated with IDH1 mutation (R132H/C/G/S). Methylation profiling identified a subtype of GBMs called glioma-CpG island methylator phenotype (G-CIMP+ve) GBMs, and this subtype yields significant survival benefit compared to non-G-CIMP+ve GBMs and is mostly associated with IDH1 mutant GBMs. GBM biology is traditionally investigated by utilizing patient-derived tumor cells (e.g GBM stem-like cells “GSCs”) in vitro and in vivo as orthotopic xenografts in immunocompromised mouse models. However, these systems lack normal human neural tissue, and therefore the contribution of the normal human neural microenvironment is unable to be studied using these systems. This shortcoming can be addressed by utilizing human cerebral organoids (COs). Cerebral organoids are derived from induced pluripotent stem cells and can serve as in vitro model systems to recapitulate the human brain microenvironment where multiple neural cell types are represented. A recent study showed that GSCs invade and proliferate in human cerebral organoids, and these tumors phenocopy parental tumors. Here, we hypothesized that the invasiveness of GSCs within COs is dictated by IDH1 status, where IDH1 wild-type are more aggressive than IDH1 mutant GSCs. To test our hypothesis, we utilized 45 day-old COs and three GSCs lines (2 IDH1 wild-type and 1 IDH1 mutant) for in vitro invasion and proliferation assays. These GSCs stably express either green or red fluorescent proteins and can be used as surrogates to identify GSCs within COs. Upon co-incubation for various time points, these GSC bearing COs were fixed, embedded, sectioned, and imaged with a confocal microscope. Our preliminary results show that GSCs with wild-type IDH1 appear to be more aggressive within COs. With further research studies, the use of COs will elucidate the contribution of the normal brain microenvironment to the growth and invasiveness of GBMs. Citation Format: Maxime Munyeshyaka, Sanjay Singh, Joy Gumin, Jing Yang, Daniel Ledbetter, Frederick Lang. Invasive properties of GSCs with known IDH1 status into human cerebral organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3907.