PATH-60. BRAIN TUMORS: FROM ONCOSTREAMS TO LIQUID CRYSTALS

Abstract

Abstract High grade gliomas (HGG) are the most common, destructive, and varied of all malignant brain tumors. HGG are heterogeneous at the histological, cellular, and molecular level, which makes them hard to study and treat. One particular tumor pathological differentiation is mesenchymal differentiation, containing oblong, motile cells. We recently noted distinct fascicles of elongated, aligned, mesenchymal-like cells in mouse and human gliomas, which we denote as oncostreams. Time-lapse confocal microscopy in ex vivo slices, and in in vivo two photon imaging, indicated that cells in oncostreams are motile. Oncostream motility was classified based on cellular orientation. The molecular characteristics of oncostreams were determined by laser capture microdissection, RNA-sequencing, and bioinformatics. 43 genes were differentially expressed; COL1A1 was overexpressed in oncostreams. Inhibition of COL1A1 in mouse gliomas, using the Sleeping Beauty transposon model, reduced oncostreams, tumor aggressiveness, proliferation, tumor vasculature, and collective glioma invasion. More recently, we elucidated that glioma cell growth in vitro, and potentially in vivo displays domains of nematic orientation (oncostreams) and topological defects, suggesting that gliomas are organized as liquid crystals. Topological defects are singularities of local orientation, and characteristic of liquid crystals. Further, studies of gliomas in vivo, suggest the presence of ±1/2 topological defects. Thus, nematic orientation and topological defects are present in brain tumors in vitro and in vivo. This provides support for our hypothesis that brain tumors are organized as active liquid crystals. As topological defects have been exploited to alter liquid crystal behavior, we hypothesize that manipulating brain tumor liquid crystalline behavior will be of therapeutic importance. Comba et al. (2022) Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression. Nature Communications: Wood et al. (2023) Scale-free correlations and potential criticality in weakly ordered populations of brain cancer cells. Science Advances (in press).