Proof‐of‐Concept in a 3D Culture Model of Glioma Invasion: Towards Personalized Therapeutics in Brain Cancer

Abstract

Glioma is a highly aggressive form of brain cancer, with some subtypes having 5‐year survival rates of less than 5%. Tumor cell invasion into the surrounding parenchyma seems to be the primary driver of these poor outcomes, as most gliomas recur within 2 cm of the original surgically‐resected tumor. Many current approaches to the development of anticancer therapy attempt to target genetic weaknesses in a particular cancer, but may not take into account the microenvironment experienced by a tumor and patient‐specific genetic differences in susceptibility to treatment.The primary aim of our research program is to overcome these limitations by ultimately developing 3D cerebral organoids generated from patient‐derived induced pluripotent stem cells (iPSCs), in which we will screen to identify an optimal treatment regimen by combining the organoids with patient‐derived tumor cells. As a proof‐of‐concept of this approach, we developed a system in which we could model the invasion of human glioma cells into mouse neural progenitor cell‐derived spheroids. Here we demonstrate the utility of such an approach, and find that we can follow invasion of human tumor cells using cell tracking dyes and 3D laser scanning confocal microscopy, both in real time and in fixed samples. These results were validated using conventional cryosectioning. We go on to show broad applicability of this system by using two different tumor cell lines, and two different mouse genetic backgrounds, attempting to mimic differences that might be observed in tumor and patient brain tissue, respectively. Having obtained this proof‐of‐concept, we will next recapitulate these results in a fully humanized system using spheroids and then cerebral organoids from human iPSCs, before moving on to patient‐derived cultures. This stepwise approach could ultimately lead to truly personalized treatments for brain cancer.Support or Funding InformationDvP is supported by the UBC Faculty of Medicine, the UBC Summer Student Research Program, and the Mach‐Gaensslen Foundation. CCN is supported by the Canada Research Chair program and a grant from the Canadian Cancer Society. WCS is supported by the Canadian Cancer Society.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.