Biology subjects

Dzhivhuho, G. A.

Publications and source records attributed to Dzhivhuho, G. A..

3 recordsLinked to original sources

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↗

bioRxiv2025

SMARCA4 is essential for early-stage tumor development but its loss promotes late-stage cancer progression in small-cell lung cancer

SMARCA4 and other components of the SWI/SNF chromatin remodeling complex have been implicated in various cancers. Yet, its role in small cell lung cancer (SCLC) tumorigenesis remains poorly understood. Genetically engineered mouse models (GEMMs) of SCLC revealed that deletion of Smarca4 significantly decreased tumor development in this model. Pharmacological inhibition of SMARCA4 decreased the proliferation of preneoplastic neuroendocrine (NE) cells. These effects coincided with reduced expression of the lineage-specific transcription factor, ASCL1, suggesting that disruption of the SMARCA4-ASCL1 axis impairs tumor development. However, Smarca4-deficient tumors, albeit smaller than controls, displayed features associated with malignant progression, including variant histology and the loss of NE differentiation. This prompted us to test the functional role of SMARCA4 in established tumor cells that recapitulate late-stage disease. Intriguingly, whilst Smarca4 knockdown in tumor cells failed to affect their proliferative capacity in vitro, Smarca4 knockdown tumors exhibited enhanced growth following subcutaneous transplantation in athymic nude mice. Interestingly, SMARCA4 knockdown significantly reduced expression and cell-surface display of PVR, a ligand for activating natural killer (NK) cells. These results led to an idea that the enhanced tumor formation was partly owing to altered tumor-NK cell interactions mediated by the SMARCA4-PVR axis in tumor cells. These findings suggest that SMARCA4 plays a temporally distinct role in SCLC, supporting early tumorigenesis but potentially functioning as a tumor suppressor in the later stages. The dramatic differences observed when targeting SMARCA4 in distinct disease states emphasize a need to acknowledge how differences in the timing of alterations can drastically alter tumor evolution.

cancer biology↗

bioRxiv2025

Rev-RRE activity modulates HIV-1 replication and latency reactivation: Implications for viral persistence and cure strategies

The HIV-1 Rev-RRE regulatory axis plays a crucial role in viral replication by facilitating the nucleo-cytoplasmic export and expression of viral mRNAs with retained introns. In this study, we investigated the impact of variation in Rev-RRE functional activity on HIV-1 replication kinetics and reactivation from latency. Using a novel HIV-1 clone with an interchangeable Rev cassette, we engineered viruses with different Rev functional activities and demonstrated that higher Rev-RRE activity confers greater viral replication capacity while maintaining a constant level of Nef expression. In addition, a low Rev activity virus rapidly acquired a compensatory mutation in the RRE that significantly increased Rev-RRE activity and replication. In a latency model, proviruses with differing Rev-RRE activity levels varied in the efficiency of viral reactivation, affecting both initial viral release and subsequent replication kinetics. These results demonstrate that activity differences in the Rev-RRE axis among different viral isolates have important implications for HIV replication dynamics and persistence. Importantly, our findings indicate that bolstering Rev/RRE activity could be explored as part of latency reversal strategies in HIV cure efforts. Author SummaryThe activity of the HIV-1 Rev-RRE axis is essential for viral replication and varies among primary viral isolates. However, the role of this for viral fitness, evolution, and persistence has not previously been investigated. Our results show that during in vitro replication, there is a selective fitness advantage for viruses with higher Rev-RRE activity and that HIV has the ability to fine tune this regulatory system with minimal sequence changes. Additionally, the maintenance of Nef expression in low Rev activity viruses suggests a potential mechanism for balancing immune evasion and replication capacity in different selection landscapes within a host. We also show that viruses with low Rev-RRE activity are more difficult to reverse from latency than viruses with higher Rev-RRE activity. Thus, differences in provirus Rev-RRE activity may be a barrier to developing effective latency reversal strategies. These findings provide new insights into the complex roles that the Rev/RRE axis plays in functionality, viral fitness, evolution, and persistence.

microbiology↗