Biology subjects

Ozturk, E.

Publications and source records attributed to Ozturk, E..

11 recordsLinked to original sources

bioRxiv2026

Matrix-modulated Air-liquid Interface Microenvironments Reveal Architectural Control of Lung Tumor Phenotypes

Lung adenocarcinoma evolves within a highly structured microenvironment shaped by air exposure, basement-membrane ligands and three-dimensional (3D) organization, yet standard in vitro models capture only fragments of this architecture. Here, we systematically disentangle how air-liquid interface (ALI), extracellular matrix (ECM) cues and dimensionality interact to regulate tumor epithelial states. Using five architectural configurations, we demonstrate that these parameters act synergistically to promote distinct morphological, transcriptional and inflammatory phenotypes not observed under conventional 2D or submerged 3D cultures. ALI broadly enhanced epithelial cohesion, progenitor activation, partial EMT programs and cytokine expression, whereas ECM embedding further induced ALI-mediated mesenchymal activation, matrix remodeling and invasive cytoskeletal organization. Notably, 3D ALI uniquely produced a hybrid alveolar-mucinous phenotype characterized by concurrent SP-C and MUC5B induction, alongside integrated epithelial, basal and mucosecretory identities. These emergent states reflect tumor-relevant plasticity and illuminate architectural controls over lineage infidelity, invasion and inflammatory activation. Together, these findings establish ALI-ECM-dimensionality intersections as critical regulators of lung tumor phenotype and provides a systematic architectural framework for designing more physiologically relevant in vitro lung cancer models.

bioengineering↗

bioRxiv2026

Rapid and efficient generation of human 8-cell-like cells for embryo modelling

8-cell blastomeres of human embryos possess broad lineage potential and undergo major zygotic genome activation (ZGA), yet experimental access to this transient cell state remains limited. Rare 8-cell-like cells (8CLCs) arise spontaneously in naive pluripotent stem cell cultures, but their low abundance has constrained mechanistic and functional studies. Here, we develop a chemically defined strategy for rapid and robust induction of 8CLCs. Through sequential small-molecule screens focused on chromatin regulators, we identify five compounds acting through distinct pathways that generate up to 40% 8CLCs within 48 hours. The resulting cells, which we term rapidly induced 8CLCs (ri8CLCs), recapitulate key molecular features of 8-cell blastomeres, including induction of ZGA-associated genes, cleavage-stage transposable elements, and 8-cell-stage transcriptional signatures in bulk and single-cell transcriptomic analyses. Functionally, ri8CLCs exhibit enhanced developmental competence, acquiring the ability for spontaneous extraembryonic differentiation and assembly into well-cavitated blastoids on an accelerated 72-hour timeline. Notably, ri8CLC induction enables blastoid formation even in the absence of MEK inhibition, TGF-{beta}/Activin/Nodal inhibition and exogenous LIF, revealing a developmental competence consistent with an early embryonic state. Together, these findings establish a rapid, defined, and highly efficient platform for generating human ri8CLCs and provide a tractable model for studying early human embryogenesis.

developmental biology↗

bioRxiv2026

Engineered Matrices Reveal Sulfation-Mediated Stress Adaptation and Drug-Specific Modulation of Chemotherapeutic Response

Engineering biomimetic extracellular matrices that isolate specific biochemical cues is essential for understanding how matrix chemistry regulates tumor cell behavior and therapeutic response. Aberrant sulfation due to proteoglycan expression is a hallmark of lung tumor matrices, yet its functional impact is difficult to study using conventional materials where mechanical and biochemical variables are coupled. To address this, mechanically matched sulfated alginate hydrogels are engineered to mimic the elevated sulfated glycosaminoglycan (sGAG) content of malignant ECM, enabling sulfation to be examined as a single, tunable variable. Within this system, ECM sulfation is shown to enhance tumor cell proliferation, promote oxidative and mitochondrial stress tolerance, suppress apoptotic signaling and attenuate the efficacy of cisplatin, gemcitabine and paclitaxel. Sulfated matrices preserve mitochondrial membrane potential, limit ROS accumulation, shift apoptotic gene expression toward a survival-favoring profile, selectively upregulate ABCB1-mediated efflux and modulate drug response through the PI3K/Akt-ABCB1 signaling axis. Functional inhibition of PI3K and ABCB1 uncovers drug-specific dependencies while dual pathway targeting completely restores chemotherapeutic sensitivity. These findings identify ECM sulfation as a potent regulator of stress adaptation and therapeutic efficacy in lung adenocarcinoma and underscore the importance of biomimetic ECM design in controlling tumor cell fate and drug response.

bioengineering↗

bioRxiv2025

MetaboFM: A Foundation Model for Spatial Metabolomics

Mass spectrometry imaging (MSI) provides molecularly resolved maps of metabolites and lipids across tissues, yet the lack of large-scale, unified representation learning frameworks limits its potential for generalization and downstream analysis. Here, we introduce MetaboFM, a foundation model for spatial metabolomics that consolidates thousands of public MSI datasets into standardized spatial-spectral tensors and extracts transferable embeddings using pretrained Vision Transformers. We curated and standardized around 4000 publicly available MSI datasets from the METASPACE repository, spanning multiple organisms, tissue types, ionization modes, and instruments. Across six metadata prediction tasks--encompassing organism, ionization polarity, tissue type, condition, analyzer type, and ionization source embeddings from pretrained MetaboFM encoders achieved a mean macro-F1 of 0.74 and accuracy of 0.80 with linear probes, demonstrating substantially higher discriminative power than classical principal component analysis (PCA) or randomly initialized baselines by over 20 percentage points. To interpret the learned representations, we mapped embedding directions back to the m/z domain, revealing distinct spectral regions that drive class separation across tissues, conditions, and ionization sources. A multimodal visual question answering (VQA) extension further links MSI embeddings with natural-language queries through a cross-attention fusion module, attaining an average macro-F1 of 0.61 {+/-} 0.05 across tasks. Finally, an interactive Gradio interface enables users to visualize MSI patches and query sample metadata in free-form language. Together, MetaboFM establishes a scalable foundation model paradigm for MSI, unifying representation learning, spectral interpretability, and multimodal interaction within a single framework for spatial metabolomics.

bioinformatics↗

bioRxiv2025

Extracellular Matrix-Guided Tumor Stratification and Network Models Reveal Clinical Molecular Grades

The extracellular matrix (ECM) critically shapes tumor fate and treatment outcome, serving as a potent prognostic factor. Yet, its compositional heterogeneity across tumors makes it difficult to assess its impact on tumor dynamics. To address this, we introduce an ECM-guided patient stratification pipeline through integration of multi-omic data in lung cancer patients. We obtained four patient groups, representing ECM-grades that showed distinct clinical features, mutation profiles, and cellular heterogeneity. Investigation of patient-specific ECM-induced intracellular signaling via network modeling revealed strong enrichment of pathways and transcriptional regulators related to epithelial-mesenchymal transition (EMT) and cancer stemness in higher ECM-grades. Drug proximity analysis on ECM-grade specific networks predicted olaparib as an ECM-grade dependent therapeutic while erlotinib to be ECM-insensitive which were validated experimentally on lung tumor cells with distinct mutational profiles in response to differing ECM microenvironments. Overall, our ECM-mediated stratification approach is a robust system for capturing ECM heterogeneity and identifying patient groups that can be selectively targeted by distinct therapeutic strategies.

systems biology↗

bioRxiv2024

Super Resolved Single-Cell Spatial Metabolomics from Multimodal Mass Spectrometry Imaging guided by Imaging Mass Cytometry

Mass spectrometry imaging (MSI) is a powerful technique for spatially resolved analysis of metabolites and other biomolecules within biological tissues. However, the inherent low spatial resolution of MSI often limits its ability to provide detailed cellular-level information. To address this limitation, we propose a guided super-resolution (GSR) approach that leverages high-resolution Imaging Mass Cytometry (IMC) images to enhance the spatial resolution of low-resolution MSI data. By using these detailed IMC images as guides, we improve the resolution of MSI images, creating high-resolution metabolite maps. This enhancement facilitates more precise analysis of cellular structures and tissue architectures, providing deeper insights into super-resolved spatial metabolomics at the single-cell level.

systems biology↗

bioRxiv2024

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

Anelloviridae is a family of non-enveloped viruses with negative-sense, circular, single-stranded deoxyribonucleic acid (ssDNA) genomes that infect vertebrates and are a ubiquitous component of the human virome. Human anelloviruses evade induction of humoral immune responses and appear to be non-pathogenic. These properties, in conjunction with their enormous genomic diversity and wide tissue distribution, make anelloviruses compelling candidates as vectors for next-generation genetic medicines. Here we report the first gene delivery vector system based on a human commensal virus. This Anellovector is based on a virus of the Betatorquevirus genus. Production is enabled by the development of the Self-Amplifying Trans-complementation of a Universal Recombinant aNellovector (SATURN) system, which relies on a self-replicating plasmid to provide viral proteins in trans that drive replication and capsid-dependent packaging of vector genomes. The SATURN system also utilizes a Cre-lox-based recombination mechanism to generate single unit-sized circular genomes inside the MOLT-4 production cell line. We demonstrate that the SATURN system can package a vector genome from a single betatorquevirus with capsids from multiple betatorquevirus species, supporting the feasibility of establishing a novel vector platform that takes advantage of the remarkable diversity of anelloviruses. The Anellovector demonstrated function in vitro in retinal pigment epithelial (RPE) cells. The Anellovector also demonstrated durable in vivo function in the mouse eye for 9 months after subretinal administration, and achieved comparable gene expression to dose-matched adeno-associated virus 9 (AAV9) when transduced by the intracerebroventricular (ICV) route of administration. To our knowledge, this is the first report of a functional anellovirus-based gene therapy vector. Anellovectors have great potential to deliver safe, redosable, and potent therapeutics, helping to expand the reach of programmable medicines.

bioengineering↗

bioRxiv2024

Species delimitation analysis indicates cryptic speciation for Terpios gelatinosus (Porifera, Demospongiae) from coastal regions of the northeastern Mediterranean Sea

Sponges, comprising over 9000 recorded species, represent one of the most primitive groups of metazoans. Given the importance of species distribution records and the identification of new species in scientific research, these endeavors play a crucial role in enhancing ecological insights, conserving biodiversity, facilitating a better understanding of the relationships between various groups of organisms, advancing our knowledge of evolution, and potentially expanding biomedical implications. In this study, we used basic morphological data, mitochondrial Cytochrome Oxidase I (COI) gene, and Internal Transcribed Spacer two (ITS2) regions to evaluate the Terpios samples collected from four coastal sites along the northeastern Mediterranean Sea, covering a distance of approximately 450 km. For this purpose, 81 COI and 11 ITS2 records of the order Suberitida were mined from GenBank, and species delimitation analysis was performed using both the Automatic Barcode Gap Discovery method and the Poisson Tree Process (PTP), along with 11 samples from the present study. While we observed slight differences in spicule sizes, the overall morphology of all samples from our study was similar. Within the scope of this research, we report the first-ever presence record of T. gelatinosus in the northeastern Mediterranean Sea. Furthermore, we document evidence pointing to the potential existence of cryptic speciation in the region.

evolutionary biology↗

bioRxiv2023

Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness

Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed a bioengineered human lung tumor model which recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-mTOR signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We demonstrate that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors through employing integrative omics and network modeling approaches.

bioengineering↗

bioRxiv2023

Species delimitation of eight ascidian (Tunicata) species from the North Eastern Mediterranean

Members of the tunicates, a subphylum of marine filter-feeder chordates, inhabit all marine and oceanic habitats from the subtidal to the abyssal. Considered as the closest relatives to the vertebrates, the tunicates are widely used as model organisms for evo-devo, allorecognition, senescence, and whole-body regeneration studies. Yet, species boundaries are poorly understood due to high morphological and genetic plasticity that characterize many tunicates taxa. Here we study taxonomy and the distribution of eight tunicate species (Botrylloides niger Herdman, 1886/ aff. leachii, Botrylloides israeliense Brunetti, 2009, Botrylloides sp., Botrylloides anceps (Herdman, 1891), Botryllus schlosseri (Pallas, 1766), Didemnum perlucidum Monniot F., 1983, Symplegma brakenhielmi (Michaelsen, 1904) and Polyclinum constellatum Savigny, 1816) sampled from six Turkish North Eastern Mediterranean Sea sites and employed the mitochondrial barcoding marker (COI) for evaluating the relationships among geographically restricted and widely spread ascidian species. Species delimitation analysis was conducted using NCBI and the present study sequences. Morphological examinations were first done in the field and then, styelide colonies were cultured in the laboratory and studied using stereo and light microscopes. A putative new Botrylloides species (Botrylloides sp.) from the Antalya region was revealed, with 99% matching on the COI gene from Saudi Arabia, further awaiting for detailed traditional taxonomy.

genetics↗

bioRxiv2022

Human anelloviruses produced by recombinant expression of synthetic genomes.

Human anelloviruses are acquired universally in infancy, highly prevalent, abundant in blood, and extremely diverse. Their apparent lack of pathogenicity indicates that they are a major component of the commensal human virome. Despite their being extensively intertwined with human biology, these viruses are poorly understood. A major impediment in studying anelloviruses is the lack of an in vitro system for their production and/ or propagation. Here we show that the T cell-derived human cell line MOLT-4 can be transfected with plasmids comprising tandem anellovirus genomes to produce viral particles visualized by electron microscopy. We found that a previously described human anellovirus of the Betatorquevirus genus (LY2), as well as a second Betatorquevirus detected by sequencing DNA extracted from a human retinal pigmental epithelium (nrVL4619), can be synthesized and produced by these means, enabling further molecular virology studies. Southern blot was used to demonstrate replication, and site-directed mutagenesis of the viral genome was performed to show that the production of anellovirus in this cell line is dependent on the expression of certain viral proteins. Finally, experiments performed in mice using purified nrVL4619 particles produced in MOLT-4 cells demonstrated infectivity in vivo in the tissue of origin. These results indicate that anelloviruses can be produced in vitro and manipulated to improve our understanding of this viral family which is ubiquitous in humans and many other mammals. Applications of this work to gene therapy and other therapeutic modalities are currently under investigation. IMPORTANCEAnelloviruses are a major component of the human virome. However, their biology is not well understood mainly due to the lack of an in vitro system for anellovirus production and/or propagation. In this study, we used multiple orthogonal measures to show that two different anelloviruses belonging to the Betatorquevirus genus can be produced in a T-cell-derived human cell line, MOLT-4, via recombinant expression of synthetic genomes. Additionally, we show that anellovirus particles generated in this in vitro system demonstrate infectivity in vivo. Our findings enable new molecular virology studies of this highly prevalent, non-pathogenic, and weakly immunogenic family of viruses, potentially leading to therapeutic applications.

microbiology↗