MPTH-18STREAMS, VORTICES, AND NEUROSPHERES: IN VIVO NON-RANDOM LARGE SCALE SELF-ORGANIZATION OF GLIOBLASTOMA MULTIFORME AND THE ROLE OF NOVEL HISTOPATHOLOGICAL STRUCTURES

GBM (WHO IV) histological structures used in glioma diagnosis are pseudopalisades, microvascular proliferation, and necrosis. To these we can add Scherer's structures: the perivascular, perineuronal, white matter, and subpial growth of glioma cells. Though CXCL12 is important in the organization of Scherer's structures, the molecular and cellular basis of the other histopathological structures is not fully understood. To determine the large scale organization of gliomas we studied various models, including transplantable gliomas (mouse, human glioma stem cells), and genetically induced gliomas using the Sleeping Beauty Transposase system (NRas, LgT, sh-p53, PDGF, sh-ATRX, IDH1mut). Examination of all glioma models indicates the existence of streams, a hallmark of self-organization. Streams are 10-20 cells across, of various lengths, and distributed throughout the tumors. Within streams cells are fusiform and at the tumor border participate in glioma invasion. Streams can be understood mathematically using models from statistical mechanics. Experimentally, streams facilitated the migration of slower migrating glioma stem cells. We propose that streams accelerate glioma growth; inhibiting stream formation may be beneficial therapeutically. We also detected the presence of vortices in which cells appear as if rotating around a central axis. Vortices were found in murine transplantable models and in genetically induced gliomas -independently of individual genetic mutations-. Vortices can be studied mathematically using the theories of fluid dynamics. We propose that vortices are cores of glioma stem cells that nucleate brain tumor growth around them. Disrupting vortex formation could also lead to novel therapies. Our work demonstrates that gliomas display large scale, non-random, self-organization. We show the existence of novel histopathological structures in glioblastoma, and their potential role in glioma growth and invasion. We are currently working to understand their cellular, molecular, and mathematical basis as this will make them into novel so far unknown therapeutic targets.