Biology subjects

Kadara, H.

Publications and source records attributed to Kadara, H..

13 recordsLinked to original sources

bioRxiv2026

Toward Computationally Complete Spatial Omics

Multimodal spatial omics has transformed biology by mapping molecular complexity within intact tissues, yet current technologies remain limited in the number of modalities measured simultaneously and often produce lower-quality data than single-modality assays. We present COSIE, a computational framework that generates high-resolution, multilayered molecular landscapes across tissue sections, individuals, and platforms. COSIE integrates histology, epigenome, transcriptome, proteome, and metabolome into a unified representation. Applied to 12 datasets spanning 10 spatial technologies, eight modalities, and nine tissue types, ranging from thousands of spots to millions of cells, COSIE outperforms existing methods. It resolves tissue structures, enhances noisy measurements, predicts unmeasured modalities, and captures dynamic processes. In human tumors, COSIE identifies invasive subregions linked to clinical outcomes and predicts spatial gene expression in TCGA samples using only histology images. By transforming fragmented data into comprehensive spatial maps, COSIE advances computationally complete spatial omics and the creation of digital tissue twins for biomedicine.

genomics↗

bioRxiv2026

HistoSweep enables cellular-resolution tissue quality control for gigapixel images in digital pathology and spatial omics

High-resolution histology images are indispensable for pathology and increasingly serve as the structural backbone for spatial omics. Yet whole-slide images (WSIs) frequently contain artifacts, acellular voids, and background regions that, when included in computational workflows, introduce noise, degrade model accuracy, and compromise biological interpretation. Existing tools provide only coarse foreground-background separation, leaving a gap in fine-grained quality control (QC). Here we present HistoSweep, a scalable framework that generates morphology-aware tissue masks at cellular resolution. By integrating density filtering, texture descriptors, and adaptive thresholding, HistoSweep systematically removes non-informative tissue regions while preserving biologically meaningful microstructures. It processes billion-pixel WSIs in minutes on standard CPUs, requiring no GPU acceleration, and is deployable across research and clinical settings. Across 25 WSIs spanning distinct tissues, disease states, and spatial omics platforms, HistoSweep consistently outperformed existing methods. It enhanced visualization and segmentation, improved virtual cell type predictions, and safeguarded spatial transcriptomics integrity by detecting transcript leakage and transcript-histology misalignment. By enabling fine-grained, scalable QC, HistoSweep provides a foundational preprocessing step for reliable and reproducible digital pathology and spatial omics analyses.

bioinformatics↗

bioRxiv2025

Deconvolution of Sparse-count RNA Sequencing Data for Tumor Cells Using Embedded Negative Binomial Distributions

Estimating tumor-specific transcript proportions from mixed bulk samples has potential to inform novel biology. However, estimation accuracy using existing methods in sparse-count data such as microRNA-seq and spatial transcriptomics has yet to be established. We generated a mixed small RNA benchmark dataset to demonstrate analytical challenges. To resolve them, we developed DeMixNB, a semi-reference-based deconvolution model assuming a sum of negative binomial distributions. Applications to miRNA-seq from 856 patients with breast cancer and 3,755 spatial spots from lung cancer generated either clinical or mechanistic insights into tumor cell plasticity. This supports the important utility of DeMixNB to investigate cancer RNomes.

bioinformatics↗

bioRxiv2025

AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair

Facultative stem cells including lung alveolar type 2 (AT2) cells must toggle between unipotent specialization at baseline and multipotent plasticity during injury-repair. The underlying molecular switches and epigenetic changes remain unclear yet dictate regenerative versus pathological outcomes. Using multiomics and mouse genetics, we show that AP-1 members FOS, FOSB, and JUNB promote an injury-induced transitional AT2 cell state and associated chromatin landscape. Joint transcriptomic-epigenomic profiling and immunostaining distinguish CLDN4+ AT2 cells as a KRT8high subset with open chromatin highly enriched for AP-1 motifs. JUNB and FOSB accumulate in these cells upon viral injury and, along with constitutive FOS, are required for CLDN4 induction, AT2 cell dispersion, and senescence signaling toward fibroblasts, while impacting region-specific alveolar type 1 (AT1) differentiation. AP-1 activation also occurs in mouse AT2 cells expressing oncogenic Kras and transitional cells in human lung tissues with premalignant or adenocarcinoma lesions. Our work refines AT2 transitional states and reveals a gene regulatory logic shared by tissue repair and tumorigenesis. SIGNIFICANCE STATEMENTFacultative stem cells balance between their resting mode and regenerative mode. In the lung, alveolar type 2 (AT2) cells produce surfactants at baseline and, upon injury, activate to self-renew and differentiate into alveolar type 1 (AT1) cells. Such activation, observed in acute lung injury, fibrosis, and tumorigenesis, proceeds through a high-KRT8 transitional phase. Using multiomic profiling and mouse genetics, we identify activator protein-1 (AP-1) transcription factors as central regulators of a CLDN4 transitional substate, promoting AT2 cell dispersion, fibroblast signaling, and region-specific AT1 differentiation. AP-1 activation is conserved during oncogenic transformation in both mouse and human lungs. These findings refine our understanding of AT2 cell fate transition and chromatin dynamics, and reinforce a molecular connection between alveolar repair and tumorigenesis.

genomics↗

bioRxiv2025

Targeted suppression of SPP1 inhibits tumor invasion and metastasis in NRF2 hyperactivated cisplatin resistant HNSCC

PurposeCisplatin is the gold standard systemic agent for definitive treatment of HNSCC. The purpose of this study was to investigate the role of SPP1 in the progression and metastasis of cisplatin-resistant HNSCC, particularly in the context of NRF2 hyperactivation. Experimental DesignCDDP resistant HNSCC cell lines stably expressing various shRNA SPP1 constructs were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of silenced SPP1 in vitro and in vivo on CDDP sensitivity and tumor progression. Western blotting, cell invasion, functional proteomics RPPA and spatial transcriptomic analyses were performed to identify molecular interactions and metastatic signaling pathways. ResultsTargeted suppression of SPP1 improved cisplatin sensitivity, inhibited tumor invasion and metastasis in vitro and in vivo as well as several metastatic signaling proteins in NRF2- hyperactivated HNSCC. Spatial transcriptomic analysis revealed a potential mechanistic interaction between SPP1, integrins and CD44 receptors in primary and metastatic HNSCC. Spatial annotation and enrichment analyses using HALLMARK revealed gene set signatures of interferon and EMT present in cell clusters with SPP1 expression in both the primary tumor and lung metastases. Finally, increased expression of SPP1 was found to be poor prognostic factor and significantly correlated with NFE2L2/KEAP1 mutational status and higher tumor grade in HNSCC patients. ConclusionsTargeting dysregulated SPP1 improved cisplatin sensitivity, inhibited tumor invasion and metastasis in NRF2-hyperactivated HNSCC. These findings highlight the therapeutic potential of targeting SPP1 and the need for developing specific SPP1 inhibitors to improve outcomes for patients with HNSCC. Translational RelevanceCisplatin-based chemotherapy remains the standard of care for patients with locally advanced head and neck squamous cell carcinoma. Cisplatin resistance often leads to treatment failure and metastasis which accounts for the majority of mortality associated with this disease. Unfortunately, there are no effective therapeutic agents to overcome cisplatin resistance in HNSCC. Here, we present compelling evidence that targeting SPP1 (also known as osteopontin) inhibits cisplatin resistance, tumor progression and metastasis in NRF2-hyperactivated HNSCC, positioning it as a potential therapeutic target to improve treatment outcomes in HNSCC.

cancer biology↗

bioRxiv2022

Deciphering tumor ecosystems at super-resolution from spatial transcriptomics with TESLA

Recent advances in spatial transcriptomics (ST) have enabled the comprehensive characterization of gene expression in tumor microenvironment. However, ST only measures expression in discrete spots, which limits their usefulness in studying the detailed structure of TME. Here we present TESLA, a machine learning framework for multi-level tissue annotation in ST. TESLA integrates histological information with gene expression to annotate heterogeneous immune and tumor cells directly on the histology image, and further detects tertiary lymphoid structures and differential transcriptome programs between the edge and core of a tumor. TESLA provides a powerful tool for understanding the spatial architecture of the TME.

bioinformatics↗

bioRxiv2022

An atlas of epithelial cell states and plasticity in lung adenocarcinoma

Understanding cellular processes underlying early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation.

cancer biology↗

bioRxiv2021

Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

cancer biology↗

bioRxiv2020

Single-cell characterization of subsolid and solid lesions in the lung adenocarcinoma spectrum

Determining the clinical significance of CT scan-detected subsolid pulmonary nodules requires an understanding of the molecular and cellular features that may foreshadow disease progression. We studied the alterations at the transcriptome level in both immune and non-immune cells, utilizing single-cell RNA sequencing, to compare the microenvironment of subsolid, solid, and non-involved lung tissues from surgical resection specimens. This evaluation of early spectrum lung adenocarcinoma reveals a significant decrease in the cytolytic activities of natural killer and natural killer T cells, accompanied by a reduction of effector T cells as well as an increase of CD4+ regulatory T cells in subsolid lesions. Characterization of non-immune cells revealed that both cancer-associated alveolar type 2 cells and fibroblasts contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid lesions through ligand-receptor interactions. These findings suggest a decrement of immune surveillance in subsolid lesions.

cancer biology↗

bioRxiv2020

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.

cancer biology↗

bioRxiv2020

SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models

COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL, resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.

cancer biology↗

bioRxiv2020

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

genomics↗

bioRxiv2020

Specific Inhibition of GSK-3β by Tideglusib: Potential Therapeutic Target for Neuroblastoma Cancer Stem Cells

Neuroblastoma is an embryonic tumor that represents the most common extracranial solid tumor in children. Resistance to therapy is attributed, in part, to the persistence of a subpopulation of slowly dividing cancer stem cells (CSCs) within those tumors. Glycogen synthase kinase (GSK)-3{beta} is an active proline-directed serine/threonine kinase, well-known to be involved in different signaling pathways entangled in the pathophysiology of neuroblastoma. This study aims to assess the potency of an irreversible GSK-3{beta} inhibitor drug, Tideglusib (TDG), in suppressing proliferation, viability, and migration of human neuroblastoma cell lines, as well as its effects on their CSCs subpopulation in vitro and in vivo. Our results showed that treatment with TDG significantly reduced cell proliferation, viability, and migration of SK-N-SH and SH-SY5Y cells. TDG also significantly inhibited neurospheres formation capability in both cell lines, eradicating the self-renewal ability of highly resistant CSCs. Importantly, TDG potently inhibited neuroblastoma tumor growth and progression in vivo. In conclusion, TDG proved to be an effective in vitro and in vivo treatment for neuroblastoma cell lines and may hence serve as a potential adjuvant therapeutic agent for this aggressive nervous system tumor.

cancer biology↗