Biology subjects

Kushida, M.

Publications and source records attributed to Kushida, M..

4 recordsLinked to original sources

bioRxiv2026

Metabolic rewiring induces a viral mimicry-mediated quiescence in glioblastoma

Glioblastoma is a highly aggressive brain tumour driven by therapy-resistant glioblastoma stem cells (GSCs) that switch between dormant and proliferative states through poorly defined programs. In this study, we identify SAT1, encoding the rate-limiting polyamine-catabolic enzyme SSAT1, as enriched in quiescent GSCs, linking metabolic rewiring to dormancy. Pharmacologic induction of SSAT1 with the polyamine analogue N1,N11-Diethylnorspermine (DENSpm) triggers a chemoprotective, reversible growth arrest in patient-derived GSCs, independent of stemness, differentiation or senescence. SAT1-induced dormancy coincides with reduced eIF5A hypusination and global protein translation, and a marked rise in double-stranded RNA that activates type I interferon signalling. Knocking down the mitochondrial antiviral-signalling protein, essential for antiviral innate immunity, partially reverses this growth arrest, establishing viral mimicry as functionally required for dormancy. Single-cell and cohort analyses across GSCs and neural stem cells demonstrate that susceptibility to metabolically induced quiescence is set by an intrinsic inflammatory tone and lysosomal dependency, defining a context-dependent metabolic-immune axis which can be targeted to prevent GBM progression.

cancer biology↗

bioRxiv2026

Convergence on BRAF and MAPK Signaling in Glioma Development in a P53-ENU model

Pediatric high-grade gliomas (HGGs) are aggressive and lethal brain tumors that account for 15- 20% of all pediatric central nervous system (CNS) malignancies and remain largely incurable. These tumors, despite having mutational targets that activate MAPK signaling, are frequently resistant to targeted therapies in their malignant states, but often show responses when they are in lower grade form. These findings suggest a need to identify and intercept early tumorigenic events that arise in earlier tumor developmental stages. To investigate the molecular events in glioma progression, we developed and characterized a NestinCre/+;Trp53fl/fl mouse model combined with in utero exposure to the classic chemical mutagen N-ethyl-N-nitrosourea (ENU). This model mimics the context of genetic predisposition paired with an environmental genotoxic insult, and mice with loss of TRP53 in early neural precursors who are exposed to ENU at embryonic day 13.5 reproducibly develop HGGs postnatally that retain features of the human tumors. By sampling discrete lesions at premalignant, early, and late stages, we observed progressive increases in genetic complexity, stemness features, and immune signatures across tumor evolution. Notably, a recurrent Braf mutation emerged in a majority of early lesions and persisted in advanced tumors, consistent with the occurrence of BRAFV600E mutations in human gliomas that arise in children and undergo transition from lower grade to higher grade stages. Additional components of the RAS-RAF-MAPK signaling cascade, including Kras, Nras and Nf1 were found to be mutated at the late tumor stage, indicating convergent activation of this pathway in this model. Cell lines derived from early lesions responded to BRAF inhibitors, but cells from endpoint tumors were less responsive. Together, this model reveals aspects of the molecular and cellular evolution of glioma development in vivo, and identifies RAS-MAPK signaling as a critical molecular bottleneck selected for the ENU-induced mutations. This genetic-environmental model may be valuable to understanding key determinants of glioma initiation and progression, and for evaluating new therapies that limit MAPK signaling.

cancer biology↗

bioRxiv2024

Glioblastoma stem cells show transcriptionally correlated spatial organization

Glioblastoma (GBM) is an aggressive brain cancer with a poor survival rate. Despite hundreds of clinical trials, there is no effective targeted therapy. Glioblastoma stem cells (GSCs) are an important GBM model system. In culture, these cells form spatial structures that share morphological aspects with their source tumors. We collected 17,000 phase contrast images of 15 patient-derived GSC lines growing to confluence. We find that GSCs grow in characteristic multicellular patterns depending on their transcriptional state. Interpretable computer vision algorithms identified specific image features that predict transcriptional state across multiple cell confluency levels. This relationship will be useful in developing GSC screens where image features can be used to identify how GSC biology changes in response to perturbations simply by imaging cultured cells on plates.

cancer biology↗

bioRxiv2024

PRMT5 is required for full-length HTT expression by repressing multiple proximal intronic polyadenylation sites

Expansion of the CAG trinucleotide repeat tract in exon 1 of the Huntingtin (HTT) gene above a threshold of [~]36 repeats causes Huntingtons disease (HD) through the expression of a polyglutamine-expanded form of the HTT protein. This mutation triggers wide-ranging cellular and biochemical pathologies leading to cognitive, motor, and psychiatric symptoms in HD patients. As accurate splicing is required to produce the full-length HTT protein of [~]348 kDa, targeting HTT splicing with small molecule drugs is a compelling approach to lower HTT protein levels to treat HD, and splice modulators are being tested in the clinic. Here, we identify PRMT5 as a novel regulator of HTT mRNA splicing and alternative polyadenylation. PRMT5 inhibition disrupts the splicing of HTT introns 9 and 10, leading to activation of multiple proximal intronic polyadenylation sites within these introns and promoting premature termination, cleavage and polyadenylation (PCPA) of the HTT mRNA, thus lowering total HTT protein levels. We also detected increasing levels of these truncated, intron-containing HTT transcripts across a series of neuronal differentiation samples which correlated with lower PRMT5 expression. Notably, PRMT5 inhibition in glioblastoma (GBM) stem cells potently induced neuronal differentiation. We posit that PRMT5-mediated regulation of intronic polyadenylation, premature termination and cleavage of the HTT mRNA modulates HTT expression and plays an important role during embryonic development and neuronal differentiation.

neuroscience↗