Structure and function of nematic order in brain tumors

Glioblastomas (GBM) are highly aggressive brain tumors which rapidly invade into the normal brain, disrupting normal function. Our lab demonstrated earlier (Comba et al., 2022) that GBM tumors exhibit collective organization and nematic alignment which help to further tumor invasion and malignancy. We now performed further studies to elucidate the overall organization of GBM as active nematic liquid crystals. In time-lapse in-vitro cultures of brain tumor cells, we discovered the presence of two types of topological defects: comets (+1/2 charge) and trefoils (- 1/2). Defects correlated with changes in cell density and apoptosis, with -1/2 defects exhibiting decreased cell density and increased apoptosis over time. Additionally, in order to understand glioma nematic organization, we created 3D brain reconstructions from sequential sections of hematoxylin and eosin (HE) stained brain tissues from 3 unique mouse models and 4 human gliosarcoma patients. Utilizing a novel reconstruction algorithm, nematic order was calculated in the plane of the sections and also in the z-direction through the stacks of tissue. By fitting the nematic order parameter as a function of the cross-graining length scale to a power law, we determined the decay exponent and the asymptotic value of the order parameter. Interestingly, nematic alignment length scale and decay exponents correlate with tumor aggression, with more aggressive tumors exhibiting order propagation over longer distances. These results define novel physical structures in GBM, demonstrating that glioma tumors are organized with an active nematic liquid crystalline order, which we aim to exploit therapeutically in the future.