Biology subjects

Nosirov, B.

Publications and source records attributed to Nosirov, B..

4 recordsLinked to original sources

bioRxiv2026

TAOK3 inhibition constrains invasion, potentiates paclitaxel, and reprograms the tumor microenvironment toward anti-tumor immunity in cervical cancer

TAOK3 is a lesser-studied MAPK family serine/threonine kinase our group has shown to be targeted by HPV integration, suggesting a potential role in driving invasive cervical cancer (ICC). Here, we profiled TAOK3 expression in patient tumors, metastases, and cervical cancer models and localized TAOK3 within a tumor epithelial subpopulation by integrating two single-cell RNA-seq datasets. Functional consequences of TAOK3 loss were assessed with siRNA and CRISPRi in cell lines and 3D spheroids. In vivo effects were evaluated in intracervical xenografts with species-specific RNA-seq to resolve tumor versus microenvironmental responses. TAOK3 mRNA/protein were elevated in primary and metastatic ICC and primarily localized to a keratin-positive epithelial subset (T3epi) enriched for cadherin/S100 binding, vesicle/endocytic pathways, and leading-edge programs. TAOK3 silencing reprogrammed transcriptomes and proteomes toward reduced WNT/cell-cycle and motility signaling, altered endocytosis and cytoskeleton organization, and reshaped phospho-networks linked to chromatin remodeling and ERBB2-ERBB3/cytoskeletal kinase activity. Functionally, TAOK3 inhibition prolonged G2/M, suppressed invasion, and enhanced sensitivity to low dose paclitaxel. Prolonged inactivation induced methuosis-like cell death with extracellular ATP release. In xenografts, TAOK3 knockdown reduced tumor burden, downregulated KRT14--a leader cell marker--within the human tumor compartment, and enriched microenvironmental pathways for immune activation, with a specific decrease in CD206+ M2 macrophages. TAOK3 delineates an invasion-competent epithelial state in ICC and coordinates cell-cycle control, cytoskeleton-membrane dynamics, and tumor-immune crosstalk. Genetic or pharmacologic TAOK3 inhibition constrains tumor growth, potentiates paclitaxel, and remodels the microenvironment toward anti-tumor immunity, supporting TAOK3 as a potential therapeutic target and biomarker in ICC. Statement of SignificanceTAOK3 marks an invasion-competent epithelial subpopulation in cervical cancer. TAOK3 inhibition slows tumor growth, enhances chemoresponse, and reduces M2 macrophages, revealing TAOK3 as a potential therapeutic target and biomarker for patient stratification.

cancer biology↗

bioRxiv2026

Circulating immune profiling reveals impaired monocyte states and trajectories driving immunosuppression in glioblastoma

Glioblastoma (GBM) is an aggressive and lethal brain tumor marked by profound local and systemic immune dysfunction. Yet, the diagnostic and therapeutic relevance of peripheral impairments remains undefined. To clinically dissect their underlying mechanisms and pathological implications, we combined mass and flow cytometry with single-cell RNA-sequencing of peripheral blood mononuclear cells from GBM patients and healthy donors. GBM blood profiles were characterized by heterogeneous changes in classical monocytes, encompassing expanded, reduced and unchanged subsets, presenting distinct functional states, including antigen-presenting, interferon and metabolic subsets. Additional adaptations included myeloid-derived suppressor cell (MDSC) expansion and loss of non-classical monocytes. Trajectory analyses positioned MDSCs as an intermediate state, in continuum with the metabolic subset. Single-cell RNA-sequencing further showed antigen-presenting monocyte propensity to differentiate into tumor-associated macrophages. Circulating monocytes shared a "GBM-classical monocytic signature" exhibiting low MHC class II expression, altered cell-cell communication and increased anti-inflammatory mediators, such as IL1R2 and CD163. Lastly, lymphocyte alterations included decreased proportions of CD4+ T, natural killer (NK) and CD56+ T cells, retaining relatively conserved activation profiles, exemplified by up-regulation of alarmins S100A8/S100A9. These findings map systemic immune reprogramming in GBM, suggesting new avenues for non-invasive biomarker discovery and therapeutic strategies to restore anti-tumor immunity.

cancer biology↗

bioRxiv2025

Integrative multi-omics combined with functional pharmacological profiling in patient-derived organoids identifies personalized therapeutic vulnerabilities of adult high-grade gliomas

BackgroundPrecision medicine has transformed cancer treatment by tailoring therapies to specific molecular aberrations. Integrating high-resolution multi-omics with high-throughput functional profiling in patient-derived organoids of-fers a powerful strategy to further refine patient stratification. While (epi)genetic profiling has drastically improved the classification in diffuse adult gliomas, these advances have not yet translated into effective therapeutic interventions and precision medicine approaches remain to be established. Material and MethodsWe investigated a panel of 48 patient-derived organoid and orthotopic xenograft models of adult high-grade gliomas, comprehensively characterized at genomic, epigenomic and transcriptomic levels. A functional drug screen was performed on 27 organoid models using a 202-compound library targeting cancer-related pathways and epigenetic regulators. Unsupervised multi-omics factor analysis was employed to identify patient-specific therapeutic vulnerabilities. Validation included dose-dependent drug efficacy assessments, as well as biomarker assessment in patient tumors across molecular subgroups. ResultsMulti-omics analysis revealed a broad spectrum of molecular profiles capturing the genetic, epigenetic, and transcriptomic diversity of high-grade gliomas. Multi-omics factor analysis, integrating multi-omics and drug response profiles, identified distinct subgroups associated with IDH1 mutation and MYCN amplification. IDH1 mutant grade 4 astrocytomas showed selective sensitivity to histone deacetylase 3 inhibitors, while a MYCN-amplified glioblastoma responded preferentially to histone methyltransferase inhibitors. The differential drug responses were linked to specific (epi)genetic and transcriptomic biomarkers. While other glioblastomas exhibited heterogeneous treatment responses, no robust biomarker-defined responder subgroups were identified. ConclusionOur findings highlight the value of integrating multi-omics and functional profiling to inform precision medicine strategies. This approach enables the stratification of distinct patient subgroups in preclinical models, paving the way for tailored therapeutic interventions. While we observed distinct pharmacogenomic profiles in IDH1 mutant grade 4 astrocytomas and a MYCN-amplified glioblastoma, implementing precision medicine in other glioblastoma subtypes remains a substantial challenge. Key pointsO_LIIntegrating drug screening in a panel of patient-derived organoids with multi-omics enables pharmacogenomic profiling in adult diffuse high-grade gliomas C_LIO_LIIDH1 mutant grade 4 astrocytomas are sensitive to histone deacetylase 3 inhibitors C_LIO_LIMYCN-amplified glioblastoma exhibits distinct DNA methylation pattern and drug responses C_LI Study importanceTo date, attempts to develop effective precision medicine in adult high-grade gliomas failed. Here, we provide a preclinical framework for identifying personalized therapeutic by integrating multi-omics profiling with functional drug screening in patient-derived organoids. We show that IDH1 mutant high-grade astrocytomas present distinct therapeutic vulnerabilities compared to glioblastomas, linked to sensitivity to histone deacetylase 3 inhibitors. Within glioblastomas, we identified a distinct MYCN-amplified tumor, sensitive to histone methyltransferase inhibitors. Applying pharmacogenomic approaches using novel drug libraries holds promise for uncovering additional clinically relevant patient subgroups in the future. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/675145v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12c04f9org.highwire.dtl.DTLVardef@fa8872org.highwire.dtl.DTLVardef@141de6org.highwire.dtl.DTLVardef@b72086_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Adenoviral Delivery of the CIITA Transgene Induces T-Cell-Mediated Killing in Glioblastoma Organoids

The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for a successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell mediated killing of the tumor through increased activation of the immune system. Patient-based 3D GB models were infected with a replication-deficient adenovirus (AdV) armed with the Class II Major Histocompatibility Complex (MHC-II) Transactivator CIITA gene (Ad-CIITA). Successful induction of surface MHC-II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Co-culture of infected tumor cells with either PBMCs or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T-cells and the direct contact between GB and immune cells. We did not however detect evidence of activation of canonical T-cell mediated cell death pathways. While the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediated CIITA delivery to enhance T-cell-mediated immunity against GB.

cancer biology↗