Biology subjects

Mohila, C.

Publications and source records attributed to Mohila, C..

4 recordsLinked to original sources

bioRxiv2025

Mutant IDH impairs chromatin binding by PDGFB to promote chromosome instability

Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.

cancer biology↗

bioRxiv2024

Common AAV gene therapy vectors show indiscriminate transduction of living human brain cell types

The development of cell-type-specific gene therapy vectors for treating neurological diseases holds great promise, but has relied on animal models with limited translational utility. We have adapted an ex vivo organotypic model to evaluate adeno-associated virus (AAV) transduction properties in living slices of human brain tissue. Using fluorescent reporter expression and single-nucleus RNA sequencing, we found that common AAV vectors show broad transduction of normal cell types, with protein expression most apparent in astrocytes; this work introduces a pipeline for identifying and optimizing AAV gene therapy vectors in human brain samples.

bioengineering↗

bioRxiv2022

Identification of functional immune and neuronal tumor cells in glioma

Despite advances in molecular profiling, therapeutic development has been hindered by the inability to identify and target tumour-specific mechanisms without consequence to healthy tissue. Correspondingly, a computational framework capable of accurately distinguishing tumour from non-tumour cells has yet to be developed and cell annotation algorithms are unable to assign integrated genomic and transcriptional profiles to single cells on a cell-by-cell basis. To address these barriers, we developed the Single Cell Rule Association Mining (SCRAM) tool that integrates RNA-inferred genomic alterations with co-occurring cell type signatures for individual cells. Applying SCRAM to glioma, we identified tumour cell trajectories recapitulate temporally-restricted developmental paradigms and feature unique co-occurring identities. Specifically, we validated two previously unreported tumour cell populations with immune and neuronal signatures as hallmarks of human glioma subtypes. In vivo modeling revealed a rare immune-like tumour cell population resembling antigen presenting cells can direct CD8+ T cell responses. In parallel, Patch sequencing studies in human tumours confirmed that neuronal-like glioma cells fire action potentials and represent 40% of IDH1 mutant tumor cells. These studies identified new glioma cell types with functional properties similar to their non-tumour analogues and demonstrate the ability of SCRAM to identify these cell types in unprecedented detail.

cancer biology↗

bioRxiv2017

Daam2 Driven Degradation Of VHL Promotes Gliomagenesis

Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.\n\nStatement of SignificanceWe found that the glial developmental factor Daam2 promotes glioma tumorigenesis by suppressing VHL expression. Our studies show, for the first time, a regulatory mechanism that operates upstream of VHL in cancer and provides an explanation for how VHL expression is extinguished in tumors that do not have inactivating mutations.

cancer biology↗