Biology subjects

Zacharias, L.

Publications and source records attributed to Zacharias, L..

4 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2025

Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

cancer biology↗

bioRxiv2024

Evolution of the meiotic recombination pathway in vertebrates

Meiotic recombination is an integral cellular process, required for the production of viable gametes, and the rate at which it occurs is a fundamental genomic parameter, modulating how the genome responds to selection. Our increasingly detailed understanding of its molecular underpinnings raises the prospect that we can gain insight into trait divergence by examining the molecular evolution of recombination genes from a pathway perspective, as in mammals, where protein-coding changes in the later stages of the recombination pathway are connected to divergence in intra-clade recombination rate. Here, we leveraged increasing availability of avian and teleost genomes to reconstruct the evolution of the recombination pathway across two additional vertebrate clades: birds, which have higher and more variable rates of recombination and similar divergence times to mammals; and teleost fish, which have much deeper divergence times. We found that the rates of molecular evolution of recombination genes are highly correlated between vertebrate clades, suggesting that they experience similar selective pressures. However, recombination genes in birds were significantly more likely to exhibit signatures of positive selection, unrestricted to later stages of the pathway. There is a significant correlation between genes linked to recombination rate variation in mammalian populations and those with signatures of positive selection across the avian phylogeny, suggesting a link between selection and recombination rate. In contrast, the teleost fish recombination pathway is more highly conserved with significantly less evidence of positive selection. This is surprising given the high variability of recombination rates in this clade.

evolutionary biology↗

bioRxiv2020

1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few notable exceptions, their identities remain largely unknown. We uncovered the immune regulatory metabolic states and metabolomes of sorted tumor and stromal, CD4+, and CD8+ cells from the tumor and ascites of patients with high-grade serous ovarian cancer (HGSC) using high-dimensional flow cytometry and metabolomics supplemented with single cell RNA sequencing. Flow cytometry revealed that tumor cells show a consistently greater uptake of glucose than T cells, but similar mitochondrial activity. Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the gene encoding the enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Treatment of T cells with MNA resulted in an increase in T cell-mediated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Thus, the TME-derived metabolite MNA contributes to an alternative and non-cell autonomous mechanism of immune modulation of T cells in HGSC. Collectively, uncovering the tumor-T cell metabolome may reveal metabolic vulnerabilities that can be exploited using T cell-based immunotherapies to treat human cancer.

immunology↗