Biology subjects

Kaur, H.

Publications and source records attributed to Kaur, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Pathobiont-triggered induction of epithelial IDO1 drives regional susceptibility to Inflammatory Bowel Disease

The structure and function of the mammalian gut vary by region, yet why inflammatory diseases manifest in specific regions and not others remains unclear. We use a TNF-overexpressing Crohns disease (CD) model (Tnf{Delta}ARE/+), which typically presents in the terminal ileum (TI), to investigate how environmental factors interact with the hosts immune susceptibility to drive region-specific disease. We identified Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as necessary and sufficient to trigger disease manifestation in the ascending colon (AC), another common site of human CD. Disease manifestation in the AC depends on indoleamine 2,3-dioxygenase (IDO1) activity induced by hypersensitive surface secretory cells in genetically susceptible hosts. Single-cell and microbial analyses of human specimens also implicates this pathobiont-epithelial IDO1 pathway in patients with a history of CD in the AC. Our findings demonstrate that genetic and microbial factors can independently drive region-specific disease and provide a unique model to study CD specific to the AC.

cell biology↗

bioRxiv2024

Shapes of Plasma Membrane Vesicles and PC-Cholesterol Vesicles Reveal Their Effective Spontaneous Curvature

Giant membrane vesicles (GUVs) and giant plasma membrane vesicles (GPMVs) are useful models for studying cellular membrane properties. Our research analyzed the reduced volume of vesicles made from phospholipid and 10% cholesterol to investigate transbilayer sugar asymmetries. We found that GPMVs have an average reduced volume of (0.88 {+/-} 0.06) with buffer asymmetry of 323 mM, lower than the (0.92 {+/-} 0.08) observed for DOPC: cholesterol vesicles with sucrose/glucose asymmetry of 390 mM. GUVs with different sugars inside and outside were more deflated, demonstrating a greater volume reduction than those with the same sugar inside and out. We applied the area-difference elasticity (ADE) model to map GPMVs and used the spontaneous curvature (SC) model to analyze DOPC: cholesterol GUVs, extracting spontaneous curvature based on their reduced volume. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/622000v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@178828forg.highwire.dtl.DTLVardef@c38f8eorg.highwire.dtl.DTLVardef@105c783org.highwire.dtl.DTLVardef@6da36d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Post-transcriptional regulation of cyclin A and cyclin B mRNAs is mediated by Bruno 1 and Cup, and further fine-tuned within P-bodies

Cell cycle progression is tightly controlled by the regulated synthesis and degradation of Cyclins, such as Cyclin A and Cyclin B, which activate CDK1 to trigger mitosis. Mutations affecting Cyclin regulation are often linked to tumorigenesis, making the study of cyclin mRNA regulation critical for identifying new cancer therapies. In this study, we demonstrate via super-resolution microscopy that cyclin A and cyclin B mRNAs associate with Bruno 1 and Cup in nurse cells. The depletion of either protein leads to abnormal Cyclin A and Cyclin B protein expression and a reduction in mRNA levels for both Cyclins. We further reveal that both cyclin A and cyclin B mRNAs accumulate in P-bodies marked by Me31B. Interestingly, Me31B is not involved in regulating cyclin A mRNA, as no changes in cyclin A mRNA levels or repression are observed upon Me31B depletion. However, cyclin B mRNA shows stage-specific derepression and reduced levels when Me31B is absent. Notably, the association between cyclin B and Cup is strengthened in the absence of Me31B, indicating that this interaction occurs independently of P-bodies. These results highlight the nuanced, mRNA-specific roles of P-body condensates in post-transcriptional regulation, challenging the idea of a uniform, binary mechanism of mRNA repression in P-bodies.

cell biology↗

bioRxiv2024

Shape analysis of biomimetic and plasma membrane vesicles

Giant membrane vesicles (GUVs) and Giant plasma membrane vesicles (GPMVs) are models for examining membrane properties. We attempted to conduct a comparative study of reduced volume of vesicles with different lipid compositions, solution symmetry, solution asymmetry, and membrane charge. The vesicular morphology is studied using three-dimensional visualization techniques. The vesicles may not be exactly similar to spheres, but they may have some fluctuations resulting in changes in their shape. To understand these shape deformations, we visualize them as confocal image stacks. Our experimental observations indicate that the charge of the membrane affects the deflation of the GUVs in the presence of trans-bilayer sugar asymmetries. The lipid bilayers of our GUVs contain a uniform distribution of the lipids in the two leaflets, which implies that the two leaflets have the same lipid composition and there is no asymmetries in this composition. However, they obtain trans-bilayer asymmetries through asymmetric adsorption or desorption layers of different solution compositions adjacent to each leaflet. The deformation of the GPMVs shapes extracted from cells with trans-bilayer buffer asymmetries and the composition asymmetries is also estimated and compared with biomimetic membranes.

biophysics↗

bioRxiv2024

PoweREST: Statistical Power Estimation for Spatial Transcriptomics Experiments to Detect Differentially Expressed Genes Between Two Conditions

Recent advancements in Spatial Transcriptomics (ST) have significantly enhanced biological research in various domains. However, the high cost of current ST data generation techniques restricts its application in large-scale population studies. Consequently, there is a pressing need to maximize the use of available resources to achieve robust statistical power. One fundamental question in ST analysis is to detect differentially expressed genes (DEGs) among different conditions using ST data. Such DEG analysis is often performed but the associated power calculation is rarely discussed in the literature. To address this gap, we introduce, PoweREST (https://github.com/lanshui98/PoweREST), a power estimation tool designed to support power calculation of DEG detection with 10X Genomics Visium data. PoweREST enables power estimation both before any ST experiments or after preliminary data are collected, making it suitable for a wide variety of power analyses in ST studies. We also provide a user-friendly, program-free web application (https://lanshui.shinyapps.io/PoweREST/), allowing users to interactively calculate and visualize the study power along with relevant the parameters.

bioinformatics↗

bioRxiv2024

Impact of Species-Specific Plant Growth-Promoting Rhizobacteria (PGPR) on Maize (Zea mays) Phenotypic and Biochemical Diversity

Maize (Zea mays) is a vital cereal crop used as a staple diet in many countries. In contemporary farming practises, inoculation with plant-growth-promoting rhizobacteria (PGPR) can be promoted as a sustainable alternative to chemical fertilizers and pesticides in cereal crops including maize. For experimental verification of the above-mentioned hypothesis, four PGPR inoculants Pseudomonas fluorescens, P. putida, Azospirillum lipoferum and Bacillus subtilis were applied to three maize genotypes (AXE*, PMH1 and PMH10) and their effects were studied by measurement of various morphological and biochemical paramters. Substantial increase in the amount of chlorophyll a (45%), chlorophyll b (100%), total chlorophyll (95%), nitrate reductase (22%), superoxide dismutase (52%), protein content (16%), methionine content (31.8%), grain protein content (69%) were recorded over the control (non-treated or mock) plants. Morphological parameters also exhibited an increase in leaf number (53%), fresh weight (41%) and dry weight (62%) in test plants. Comparable outcome was observed for whole cob weight showing an increase of 42%, cob weight (60%), hundred-grain weight (25.9%), maize grain yield m-2 (18%) and yield ha-1 (18%) over the control. This study highlights the efficacy of the aforementioned four PGPR species as the most effective for maize crops. Bacillus subtilis and Azospirillum lipoferum may be considered species-specific PGPRs due to their superior performance compared to other strains. The considerable growth-promoting advantages observed in maize plants treated with bacterial inoculation indicated that PGPRs have the potential to be employed as sustainable solutions in maize production.

plant biology↗

bioRxiv2024

An experimental approach to study multi-species diseases interactions in wheat using machine learning-aided image analysis

Fusarium Head Blight (FHB) is a major disease of cereal crops present everywhere where wheat is produced. A complex of several, distinctly different, species from the genus Fusarium are responsible for causing the disease, with important taxa being F. graminearum, F. culmorum, and F. avenaceum. FHB is an adult stage, late season disease affecting wheat at anthesis. However, recent discoveries are now challenging the basic assumption that anthers and spikes are the only ecological niches relevant for resistance to FHB. Most prominently, it has been established that pathogens typically occurring earlier in the season, such as Zymoseptoria tritici, induce strong systemic changes in the plant immune system, that expand way beyond their primary ecological niche. Furthermore, taxa implicated in FHB can be isolated from virtually all wheat tissues, including typical blotch symptoms on wheat leaves. Strikingly, such important biological observations about the complex lifestyle of FHB causing taxa are overlooked as potential targets in resistance breeding. In this work we present a simplified approach allowing the dissection of the intricate lifestyles of the FHB causing Fusarium taxa. In doing so, we provide an experimental proof-of-concept that systemic signals from Z. tritici can affect the basic response of wheat to F. graminearum. We further demonstrate that differences in Fusarium species composition affect the outcome of the interaction in a genotype-specific manner. We argue that efforts to study hidden layers of the biology of FHB associated taxa are crucial to developing new resistance breeding strategies, based on a better understanding of the genetic drivers of the disease.

plant biology↗

bioRxiv2024

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1

Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+), but only those with Rb1 deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. Importantly, we show this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture. By integrating multiplexed immunofluorescence, spatial transcriptomics and PrismSpot to identify cell type-specific spatial gene modules, we reveal that ASCL1+ cells arise from KRT8+ luminal epithelial cells that progressively acquire transcriptional heterogeneity, producing large ASCL1+;KRT8- NEPC clusters. Ascl1 loss in established NEPC results in transient tumor regression followed by recurrence; however, Ascl1 deletion prior to transplantation completely abrogates lineage plasticity, yielding adenocarcinomas with elevated AR expression and marked sensitivity to castration. The dynamic feature of this model reveals the importance of timing of therapies focused on lineage plasticity and offers a platform for identification of additional lineage plasticity drivers.

cell biology↗

bioRxiv2024

CD14 Blockade Does Not Improve Outcomes of Deep Vein Thrombosis Following Inferior Vena Cava Stenosis in Mice

BackgroundNeutrophil-mediated persistent inflammation and neutrophil extracellular trap formation (NETosis) promote deep vein thrombosis (DVT). CD14, a co-receptor for toll-like receptor 4 (TLR4), is actively synthesized by neutrophils, and the CD14/TLR4 signaling pathway has been implicated in proinflammatory cytokine overproduction and several aspects of thromboinflammation. The role of CD14 in the pathogenesis of DVT remains unclear. ObjectiveTo determine whether CD14 blockade improves DVT outcomes. MethodsBulk RNA sequencing and proteomic analyses were performed using isolated neutrophils following inferior vena cava (IVC) stenosis in mice. DVT outcomes (IVC thrombus weight and length, thrombosis incidence, neutrophil recruitment, and NETosis) were evaluated following IVC stenosis in mice treated with a specific anti-CD14 antibody, 4C1, or control antibody. ResultsMice with IVC stenosis exhibited increased plasma levels of granulocyte colony-stimulating factor (G-CSF) along with a higher neutrophil-to-lymphocyte ratio and increased plasma levels of cell-free DNA, elastase, and myeloperoxidase. Quantitative measurement of total neutrophil mRNA and protein expression revealed distinct profiles in mice with IVC stenosis compared to mice with sham surgery. Neutrophils of mice with IVC stenosis exhibited increased inflammatory transcriptional and proteomic responses, along with increased expression of CD14. Treatment with a specific anti-CD14 antibody, 4C1, did not result in any significant changes in the IVC thrombus weight, thrombosis incidence, or neutrophil recruitment to the thrombus. ConclusionThe results of the current study are important for understanding the role of CD14 in the regulation of DVT and suggest that CD14 lacks an essential role in the pathogenesis of DVT following IVC stenosis.

pathology↗

bioRxiv2024

Survey of the wheat mycobiome associated with leaf blotch and head blight diseases in Sweden

Increasing the durability of crop resistance to plant pathogens has become a major concern in plant pathology. There are 32 diseases of agronomical importance in wheat, which makes disease management in this crop of worldwide importance extremely challenging. Two important groups of wheat pathogens driving the consumption of chemical fungicides in Sweden and worldwide are those causing head blight diseases and leaf blotch diseases. Swedish fields are regularly infested with head blight diseases typically driven by a complex of Fusarium and non-fusarium taxa including F. graminearum, F. culmorum, while leaf blotches are typically caused by Zymoseptoria tritici, Pyrenophora tritici-repentis, and Parastagonospora nodorum. In this work, we present a survey of the larger diversity of taxa associated with head blight and leaf blotch diseases in Sweden, with the primary aim to assess the usefulness of such an approach to develop new understanding and tools for disease diagnostics and management sensu lato. Here, we analyze nearly a thousand isolates collected from wheat fields across eight counties in Sweden and report the identification of pathogenic and non-pathogenic taxa as well as candidate biological control agents associated with head blight and leaf blotch diseases. We argue that such surveys represent an important tool for improving disease diagnostics, disease forecasting, and integrated management in wheat.

plant biology↗

bioRxiv2023

Sequence types of Enteroaggregative Escherichia coli strains recovered from human, animal, and environmental sources, India.

ObjectivesIn the current study, we report whole genome sequencing (WGS) data on EAEC strains from India to identify lineages and different sequence types (STs) in our geographical regions across North India. Material and methodsWe performed WGS comparative genomics characterization to examine the diversity of 122 EAEC strains collected from a large geographic area from clinical (Human sources) and non-clinical sources (animal and environmental sources). M-PCR for 21 virulence genes was performed. A triplex PCR detected phylogenetic groups A, B1, B2, and Dwas done. All strains were genome-sequenced, and bioinformatics analysis was performed. ResultsEAEC isolates belonged to 29 sequence types, further clustered into 11 clonal complexes, among which CC38 was the largest, containing 38 isolates mainly belonging to two ST types (ST38 and ST315). CC10 was the most diverse group, comprising 8 STs (ST43, ST2706, ST1286, ST 10, ST167, ST34, ST227, and ST4305). The most frequently detected virulence gene among the 96 clinical EAEC isolates was astA (87.5%), followed by ORF3 (62.5%), and aap (54.1%). ConclusionThese findings indicate the high diversity of EAEC and different sources of unique ST types of EAEC. Such genetic relatedness may be a favorable factor in exchanging virulence factors and other genes. The results of this study provide genetic evidence that farmed animals may act as a reservoir of EAEC.

genomics↗

bioRxiv2023

A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn's Disease

Crohns disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohns ileitis and Crohns colitis and identify novel biomarkers associated with disease activity and treatment response.

bioinformatics↗

bioRxiv2023

Alpha-synuclein expression in neuron modulates the Japanese encephalitis virus infection

Japanese encephalitis virus (JEV) stands as a prominent vector-borne zoonotic pathogen, displaying neurotropism and eliciting Parkinsons disease (PD)-like symptoms among most symptomatic survivors. A characteristic feature of PD is aggregation of mutated -synuclein (-syn) that damages the dopaminergic neurons. Considering this link between JEV-induced PD-like symptoms and -syn pathogenesis, we explored the role of -syn in JEV infectivity in neuronal cells. Our investigation revealed significant increase in endogenous -syn expression in JEV-infected cells. Additionally, treatment with exogenous -syn (Exo-syn) led to a substantial reduction in JEV replication, suggesting its anti-JEV effect. Furthermore, Exo-syn treatment led to the upregulation of superoxide dismutase 1 (SOD1) and reduction in reactive oxygen species (ROS). The results were validated by endogenous -syn-silencing, that decreased SOD1 level and raised ROS level in neuronal cells. Similarly, the SOD1 inhibition via LCS-1 also intensified ROS and JEV infection. Overall, our results suggest that -syn exerts an anti-JEV effect by regulating protein involved in oxidative stress inside neuronal cells. This study contributes valuable insights into the interplay between -syn expression and JEV infectivity, shedding light on avenues to further investigate the potential role of -syn in JEV pathogenesis. ImportanceJapanese encephalitis virus (JEV) poses significant threat particularly to children. Despite extensive research efforts, the development of effective treatments against JEV has been impeded. One of the major setbacks is a lack of comprehensive understanding of neurotropism. The study focuses on alpha synuclein (-syn), a neuronal protein, and aims to determine its role in JEV pathogenesis. Present study reveals that host cell upregulates -syn in response of JEV infection. -syn restrains JEV propagation by modulating superoxide dismutase 1 (SOD1) expression which further blocks JEV-induced ROS generation. Endogenous -syn silencing led to decrease in SOD1 expression and increased viral titer. -syn plays crucial role in counteracting oxidative stress through SOD1, which is essential for limiting JEV replication. This study provides broader implications for antiviral strategies and its possible role in neurodegenerative diseases; however, there is still much to explore, particularly regarding its aggregation kinetics in JEV infection.

microbiology↗

bioRxiv2023

GammaGateR: semi-automated marker gating for single-cell multiplexed imaging

MotivationMultiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data. ResultsTo address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation. Availability and ImplementationThe R package is available at https://github.com/JiangmeiRubyXiong/GammaGateR. ContactPlease address correspondence to jiangmei.xiong@vanderbilt.edu and simon.vandekar@vumc.org. Key PointsO_LIGammaGateR is the first semi-automated marker gating tool for mIF image, and it will help to diminish the inconsistency with manual marker gating. C_LIO_LIWith novel cfGMM, GammaGateR can fit flexibly across slides with different distributions and incorporate biology priors. C_LIO_LIGammaGateR is proven to reveal credible prognostic information, and it can quantify known findings in tumor cell populations. C_LI

bioinformatics↗

bioRxiv2023

Correlation between plant cell wall stiffening and root extension arrest phenotype in the combined abiotic stress of Fe and Al

The plasticity and growth of plant cell walls (CWs) remain poorly understood at the molecular level. In this work, we used atomic force microscopy (AFM) to observe elastic responses of the root transition zone of 4-day-old Arabidopsis thaliana wild type and almt1 mutant seedlings grown under Fe or Al stresses. The elastic parameters were deduced from force-distance measurements by AFM using the trimechanic-3PCS framework. In all metal stresses tested, the presence of single metal species Fe2+ or Al3+ at 10 {micro}M exerts no noticeable effect on the root growth compared with the control conditions. On the contrary, a mix of both the metal ions produced a strong root extension arrest concomitant with significant increase of CW stiffness. This was not found for the almt1 mutant which substantially abolishes the ability to exude malate. By raising the concentration of either Fe2+ or Al3+ to 20 {micro}M, no root extension arrest was observed; nevertheless, a rise of root stiffness occurred. Our results indicate that the combination of Fe2+ and Al3+ with exuded malate is crucial for both CW stiffening and root extension arrest. However, stiffness increase induced by single Fe or Al metal is not sufficient for arresting root growth. Summary statementWe record the change in stiffness of the external primary cell wall of living Arabidopsis thaliana seedlings in presence of metallic stress using atomic force microscopy. Results reveals for the first time the uncoupling between mechanical response (CW stiffening) and root extension arrest.

plant biology↗

bioRxiv2023

Antibacterial activity of solid surfaces is critically dependent on relative humidity, inoculum volume and organic soiling

Antimicrobial surface materials potentially prevent pathogen transfer from contaminated surfaces. Efficacy of such surfaces is assessed by standard methods using wet exposure conditions known to overestimate antimicrobial activity compared to dry exposure. Some dry test formats have been proposed but semi-dry exposure scenarios e.g., oral spray or water droplets exposed to ambient environment, are less studied. We aimed to determine the impact of environmental test conditions on antibacterial activity against the model species Escherichia coli and Staphylococcus aureus. Surfaces based on copper, silver, and quaternary ammonium with known or claimed antimicrobial properties were tested in conditions mimicking microdroplet spray or larger water droplets exposed to variable relative air humidity in the presence or absence of organic soiling. All the environmental parameters critically affected antibacterial activity of the tested surfaces from no effect in high-organic dry conditions to higher effect in low-organic humid conditions but not reaching the effect size demonstrated in the ISO 22169 wet format. Copper was the most efficient antibacterial surface followed by silver and quaternary ammonium based coating. Antimicrobial testing of surfaces using small droplet contamination in application-relevant conditions could therefore be considered as one of the worst-case exposure scenarios relevant to dry use surfaces. Featured image + One Sentence summaryAntibacterial activity of copper and silver surfaces is highly dependent on environmental testing conditions with maximum efficiency in low-organic wet conditions to no antibacterial activity in high-organic dry conditions indicating the need to test antimicrobial surface materials in application-relevant test formats as opposed to current standards. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/534510v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@17eb30eorg.highwire.dtl.DTLVardef@11d9a72org.highwire.dtl.DTLVardef@86ea55org.highwire.dtl.DTLVardef@1828c5d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Leveraging spatial molecular information to construct a phylogeographic map of tumor evolution can reveal individualized growth trajectories with diagnostic and therapeutic potential. Integrative analysis of spatial multi-omic data from 31 colorectal specimens revealed simultaneous microenvironmental and clonal alterations as a function of progression. Copy number variation served to re-stratify microsatellite stable and unstable tumors into chromosomally unstable (CIN+) and hypermutated (HM) classes. Phylogeographical maps classified tumors by their evolutionary dynamics, and clonal regions were placed along a global pseudotemporal progression trajectory. Cell-state discovery from a single-cell cohort revealed recurring epithelial gene signatures and infiltrating immune states in spatial transcriptomics. Charting these states along progression pseudotime, we observed a transition to immune exclusion in CIN+ tumors as characterized by a novel gene expression signature comprised of DDR1, TGFBI, PAK4, and DPEP1. We demonstrated how these genes and their protein products are key regulators of extracellular matrix components, are associated with lower cytotoxic immune infiltration, and show prognostic value in external cohorts. Through high-dimensional data integration, this atlas provides insights into co-evolution of tumors and their microenvironments, serving as a resource for stratification and targeted treatment of CRC.

systems biology↗

bioRxiv2023

Consensus tissue domain detection in spatial -omics data using MILWRM

Spatially resolved molecular assays provide high dimensional genetic, transcriptomic, proteomic, and epigenetic information in situ and at various resolutions. Pairing these data across modalities with histological features enables powerful studies of tissue pathology in the context of an intact microenvironment and tissue structure. Increasing dimensions across molecular analytes and samples require new data science approaches to functionally annotate spatially resolved molecular data. A specific challenge is data-driven cross-sample domain detection that allows for analysis within and between consensus tissue compartments across high volumes of multiplex datasets stemming from tissue atlasing efforts. Here, we present MILWRM - multiplex image labeling with regional morphology - a Python package for rapid, multi-scale tissue domain detection and annotation. We demonstrate MILWRMs utility in identifying histologically distinct compartments in human colonic polyps and mouse brain slices through spatially-informed clustering in two different spatial data modalities. Additionally, we used tissue domains detected in human colonic polyps to elucidate molecular distinction between polyp subtypes. We also explored the ability of MILWRM to identify anatomical regions of mouse brain and their respective distinct molecular profiles.

systems biology↗