Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>BACKGROUND: There is emerging preclinical evidence that neuronal activity influences glioma proliferation. In humans however it remains unknown how dynamic physiological interactions between glioma cells and neurons influence tumor growth and cognition. We therefore studied the mechanisms underpinning why some glioma cells maintain functional connections with neurons and the causal relationship of these connections to tumor growth and associated cognitive impairments.</jats:p>
<jats:p>METHODS: We employed magnetoencephalography in newly diagnosed IDH-wild-type glioblastoma (GBM) patients to identify intratumoral regions with high (HFC) and low (LFC) brain functional connectivity. Site-directed patient tumor biopsies from HFC and LFC regions were used to perform immunohistochemistry experiments and generate patient-derived xenografts. Primary patient-derived neurosphere cultures were generated from HFC and LFC regions and spheroid invasion and EdU proliferation assays were performed to characterize their invasive and proliferative phenotypes, respectively. The morphology and size of HFC and LFC neurospheres was also evaluated to determine the clonogenicity profile. Secreted proteins from patient serum was measured using ELISA. Cognitive assessments and survival statistics of patients were performed to correlate with functional connectivity measures.</jats:p>
<jats:p>RESULTS: Compared to LFC, primary patient samples from HFC regions showed increased expression of pre- and post-synaptic markers. Primary patient HFC cultures co-cultured with hippocampal neurons and induced neuron organoids again demonstrated increased synaptogenesis markers. IDH-wt GBM HFC cultures demonstrated little clonogenicitiy and low proliferation however when co-cultured with neurons markedly increased their proliferative potential both in vitro and in vivo. Similarly, when compared to HFC alone and LFC conditions, the degree of cell invasion, measured by the spheroid invasion area and microtube length, was significantly increased by the addition of conditioned media from hippocampal neuronal culture. HFC IDH-wt patient derived xenografts survived a shorter time compared to LFC. Importantly, compared to patients without intratumoral high functional connectivity regions, GBM patients with intratumoral HFC showed shorter overall survival and worse cognitive task performance.</jats:p>
<jats:p>CONCLUSION: Synaptogenic glioma cells are enriched within high connectivity intratumoral regions maintains their affinity for neurons primarily through TSP-1 mediated paracrine signaling. This distinct HFC tumor sub-population exhibits an aggressive invasive and proliferative tumor phenotype, which in turn contributes to the observed adverse cognitive and survival outcomes.</jats:p>
<jats:p>Citation Format: Saritha Krishna, Abrar Choudhury, Michelle Monje, Shawn Hervey-Jumper. Glioma cells within high functional connectivity network hubs exhibit a proliferative and infiltrative tumor phenotype [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO027.</jats:p>