Dudley, L. | Search bioRxiv

bioRxiv2026

Critical role of cell competition in gliomagenesis

ABSTRACTMalignant glioma is incurable. Using a mouse genetic mosaic system to generate sporadic Trp53,Nf1-null OPCs, we previously identified oligodendrocyte precursor cell (OPC) as a cell-of-origin of glioma. Here, we report that pre-malignant Trp53,Nf1-null OPCs outcompete wildtype counterparts during their expansion. Blocking competition by mutating/strengthening wildtype OPCs impeded both pre-malignant progression and malignant expansion of glioma. "In-tissue" phosphoproteomic profiling revealed an enrichment of phosphopeptides related to RNA splicing and protein translation at the peak of cell competition, suggesting that competitiveness may stem from unique protein species. Among candidates was mTORC1, whose pharmacological inhibition or genetic disruption resulted in a loss of competitiveness in our mouse model. Finally, analysis of patient biopsies and interrogating the role of individual gliomagenic mutations in OPC competition supported its relevance in human gliomas. Together, these findings identified the driving role of competitive interactions among OPCs in gliomagenesis, and suggest unconventional therapeutic strategies to target this process.

cancer biology↗

bioRxiv2024

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, repetitive behaviors, and sensory over-responsivity in adult offspring with persistent mild brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-, ion channel-, and epilepsy-associated genes in the same time frame. Reduction of microglia with CSF1R inhibitors or inhibition of NADPH oxidase in young animals reduces the development of some of the behavioral phenotypes, but neither is as effective as acute mTOR inhibition. Our findings indicate that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD-like behaviors in adult animals without requiring long-term physical alterations to the brain. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may therefore be important targets for therapeutically addressing both primary sensory and compensatory repetitive behavior phenotypes.

neuroscience↗