GENE-33. THE 3D EVOLUTION AND IN VIVO GROWTH PATTERNS OF GLIOMA CELL POPULATIONS

Abstract

Most cancers result from multiple clonal expansion events, resulting in tumors comprised of many subclones. The coexistence of these genetically distinct populations within a single tumor is thought to underlie the failure of most current treatments. Ascertaining how diverse populations of cells evolve within tumors, and the functional implications of this diversity, are the next steps to developing more informed treatments that overcome the barrier currently posed by intratumoral heterogeneity (ITH). Previous studies of adult diffuse glioma have been restricted in their ability to provide a detailed understanding of the spatial evolution of solid tumors due to insufficient sampling, typically just one biopsy per patient, and a lack of knowledge of where within the heterogeneous tumor the sample was obtained. We have developed a unique sample collection protocol, in which we record the precise, three-dimensional (3D) coordinate for each of 10 spatially-distinct samples obtained from each patient's tumor. Whole exome data from IDH1 mutant grade II astrocytomas analyzed in this manner have revealed that expansion events are typically spatially segregated, suggesting minimal tumor-wide intermixing of subclonal cell populations in these low grade gliomas. Expression profiling of one particular case has furthermore revealed ITH of the immune microenvironment, uncovering a region of increased PD-L1 expression and IFN-gamma signaling. Ongoing analysis is focused on integrating genetic and expression profiles from these and additional spatially-mapped cases. This integrative analysis aims to dissect the relative contributions of subclonal variation and location within the tumor on gene expression patterns and ITH of the immune microenvironment. The delineation of the spatial patterns of ITH our work provides will enable more informed selection of biopsy targets in the future. It also lends greater insight into the factors shaping intratumoral variation of gene expression patterns and the immune microenvironment in adult diffuse glioma.