Biology subjects

Sirbu, O.

Publications and source records attributed to Sirbu, O..

5 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↗

bioRxiv2026

Ependymomas are cancers of the pre-neural crest/roof plate lineage

Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest/roof plate (Pre-NC/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.

developmental biology↗

bioRxiv2025

Understanding the Role of Toggle Genes in Chronic Lymphocytic Leukemia Proliferation

Cancer cell populations, such as chronic lymphocytic leukemia (CLL), are characterized by aberrant proliferation and plasticity: cells may switch between states so increasing population heterogeneity. Previous works have shown that gene expression noise can impact cell-state transition. To gain better insights into transcriptome-wide expression dynamics and the effect of noise on state transition, here we investigate RNA-Seq data of proliferative (PC) and non-proliferative (NPC) CLL cells. Various data analytics were applied to the whole transcriptome, switch-like toggle (ON/OFF) genes, temporal differentially expression (DE) genes, and randomly selected genes. Collectively, we identified 2713 temporal DE genes (DESeq2 with 4-fold, p < 0.05) and 1704 toggle genes shaping the differentiation process over a period of 96h, with 604 overlapping genes between them. Despite their lower numbers compared to DE, toggle genes contributed significantly to gene expression noise in both cell types. Toggle gene analyses revealed the enrichment of genes involved in processes such as G-alpha signaling and muscle contraction as proliferation related RHO-GTPase, interleukin and chemokine signaling, and lymphoid cell communication. Thus, toggle genes, although being random (at single cell level) ON/OFF genes, can show (at population level) a symmetry breaking favoring one of the two ON/OFF states so contributing to gene expression functional variability. These results suggest that toggle genes play an important role in shaping cell population plasticity.

genomics↗

bioRxiv2023

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

Although lifespan extension remains the gold standard for assessing interventions hypothesized to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that the use of short-lived control cohorts tends to exaggerate the relative efficacy of putative longevity interventions. Moreover, due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups. To facilitate identification of successful interventions, we propose an alternative approach. The level of confidence we can have in an intervention is proportional to the degree of lifespan extension above the strain- and species-specific upper limit of lifespan, which we can estimate from comparison to historical controls. In the absence of independent replication, a putative mouse longevity intervention should only be considered with high confidence when control lifespans are close to 900 days or if the final lifespan of the treated group is considerably above 900 days. Using this "900-day rule" we identified several candidate interventions from the literature that merit follow-up studies.

physiology↗

bioRxiv2019

The collagen-binding epitopes of Drosophila SPARC are essential for survival and collagen IV distribution and assembly into basement membranes

The assembly of basement membranes (BMs) into tissue-specific morphoregulatory structures requires non-core BM components. Work in Drosophila indicates a principal role of collagen-binding matricellular glycoprotein SPARC (Secreted Protein, Acidic, Rich in Cysteine) in larval fat body BM assembly. We report that SPARC and collagen IV (Col(IV)) first colocalize in the trans-Golgi of hemocytes. Mutating the collagen-binding epitopes of SPARC leads to 2nd instar larval lethality, indicating that SPARC binding to Col(IV) is essential for survival. Analysis of this mutant reveals increased Col(IV) puncta within adipocytes and intense perimeter Col(IV) staining surrounding the fat body as compared to wild-type larvae, reflecting a disruption in chaperone-like activity. In addition, Col(IV) in the wing imaginal disc was absent. Removal of the disulfide bridge in EF-hand2, which is known to enhance Col(IV) binding by SPARC, did not lead to larval lethality; however, a similar but less intense fat body phenotype was observed. Additionally, both SPARC mutants have altered fat body BM pore topography. Wing imaginal disc-derived SPARC did not localize within Col(IV)-rich matrices, indicating a distinct variant. Collectively, these data demonstrate the essential role of Col(IV) chaperone-like activity of SPARC to Drosophila development and indicate tissue-specific variants with differential functions.

developmental biology↗