Patterns Of Organization Research Articles

Gene co-expression networks reveal sex-biased differences in musculoskeletal ageing.

Aging is a universal and progressive process involving the deterioration of physiological functions and the accumulation of cellular damage. Gene regulation programs influence how phenotypes respond to environmental and intrinsic changes during aging. Although several factors, including sex, are known to impact this process, the underlying mechanisms remain incompletely understood. Here, we investigate the functional organization patterns of skeletal muscle genes across different sexes and ages using gene co-expression networks (GCNs) to explore their influence on aging. We constructed GCNs for three different age groups for male and female samples, analyzed topological similarities and differences, inferred significant associated processes for each network, and constructed null models to provide statistically robust results. We found that each network is topologically and functionally distinct, with young women having the most associated processes, likely due to reproductive tasks. The functional organization and modularity of genes decline with age, starting from middle age, potentially leading to age-related deterioration. Women maintain better gene functional organization throughout life compared to men, especially in processes like macroautophagy and sarcomere organization. The study suggests that the loss of gene co-expression could be a universal aging marker. This research offers insights into how gene organization changes with age and sex, providing a complementary method to analyze aging.

Unveiling drivers of conservation agriculture amidst climate challenges: A coastal Bangladeshi case study

Conservation agriculture practices play a pivotal role in augmenting agricultural productivity while concurrently fostering biodiversity, mitigating soil erosion, and enhancing plant nutrition. This study aims to delve into the determinants influencing the adoption behavior of farmers regarding conservation agriculture practices, categorizing them into medium adoption, less adoption, and non-adoption groups. Primary data were meticulously gathered from three distinct regions within the coastal areas of Bangladesh, encompassing a total of 450 respondents. Descriptive statistics were employed to delineate the socio-economic status of farmers, while multinomial logistic regression was utilized to identify factors affecting conservation agriculture adoption. This study also employed to find out the severity of different climate problem faced by the farmers. Analysis of organizational communication patterns revealed that medium adopters maintained a more substantial connection with diverse organizations compared to other groups. Descriptive statistics elucidated that both medium and less adopters of conservation agriculture had undergone more training, possessed higher farm incomes, and exhibited greater levels of education compared to non-adopters. Further exploration through factor analysis unveiled that increased training significantly influenced farmers' decisions to embrace conservation agriculture practices, concurrently enhancing their knowledge of agricultural methodologies. The study identified positive relationships between crop income, cultivable land, different channel communication exposure, climate change perception and training duration with the adoption of conservation agriculture. Finally, the results underscore the importance of organizational monitoring systems and frequent farmer engagement, alongside an augmentation in training initiatives. These measures are posited to yield more favorable outcomes in promoting conservation agriculture practices among farmers. Alongside, Conservation agriculture play a key role for achieving sustainable land use and climate action.

Abstract B076: Morphological diversity predicts functional traits in pancreatic cancer

Abstract Cell morphologies represent a phenotypic integration of intrinsic cellular processes, changes in cell state, and interactions with neighboring cells. While analyses of large cell line collections such as the Cancer Dependency Map (DepMap) have greatly enhanced discovery of novel molecular biomarkers and therapeutic targets, morphological analysis of these models has not yet been performed. Hence, there is a rich opportunity to discover novel regulators and functional properties of cell morphologies by linking image-based profiling to -omics based assays. Here, we studied the transcriptional and functional properties of 16 human pancreatic cancer cell lines, associations with distinct cell morphologies, and treatment-induced remodeling. At baseline, we observed extensive morphological heterogeneity across and within cell lines, as well as differences in multicellular organization. We categorized cell line morphologies into epithelial, mesenchymal, and spheroid, and organizational patterns into tightly aggregated, multilayered, and dispersed. We performed differential expression analysis across morphological subtypes utilizing DepMap transcriptomics data and queried functional correlates including CRISPR dependency, drug sensitivity, and proclivity for metastasis. For example, we discovered that the mesenchymal morphology and multilayered organizational pattern [WH3] were associated with metastatic potential, while expressing reduced levels of tight junction and cell adhesion genes. We then explored treatment associated morphological changes and their potential as cost-effective biomarkers for cell-intrinsic resistance to chemotherapy (e.g., 5-FU and gemcitabine) and KRAS inhibitors (e.g., MRTX1133 and RMC- 6236). Cells were treated continuously and monitored with live cell imaging (Incucyte SX5) followed by Cell Painting at the three-day endpoint. We observed conserved morphological responses to therapy across cell lines including a shift towards spindle-like cell shapes with neurite-like projections in chemotherapy-treated conditions, and a cell bloating phenomena characterized by an increase in cell area in KRAS inhibitor treated conditions. To directly link transcriptional state to morphology, we performed 1000-plex spatial molecular imaging (Nanostring CosMx) at subcellular resolution to pools of cell lines, demonstrating that morphological diversity within cell lines corresponded to distinct transcriptional states. In conclusion, this study highlights the potential of harnessing cell morphological information in a rapid, cost-effective phenotyping assay to aid precision oncology efforts leveraging patient- derived in vitro models. Citation Format: Dennis Gong, William L Hwang. Morphological diversity predicts functional traits in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B076.

Regional patterns of human cortex development correlate with underlying neurobiology

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

The loss of riparian vegetation along streams causes morphological divergences in functional traits of semiaquatic insects (Heteropteran: Gerromorpha) in the eastern Amazon.

Understanding the effects of mining activities on Amazonian streams and their impact on aquatic communities is of paramount importance in the current context of resource overexploitation in society. In this study, we assessed the significance of the environment and interspecific interactions on the organization patterns of semiaquatic insect species in a mineral extraction region in the eastern Amazon. We utilized the morpho functional characteristics of 22 species from the suborder Gerromorpha (Heteropteran), considering both the abundance and sexual dimorphism of these species. Additionally, we quantified the density of riparian vegetation surrounding each stream to categorize sampling points and evaluate whether there are differences in species distribution patterns among categories. We sampled 16 sites, categorized into two treatments based on the percentage of riparian vegetation in forested and deforested areas located in the Capim River Basin. We did not find the action of environmental filters on the total assembly; however, we found significant morphological divergence for all the traits analyzed. On the other hand, the separation of streams into treatments with different portions of riparian vegetation showed that there are significant differences between them regarding species distribution patterns. Forested streams within a 500-m radius have species distributed over a larger area, indicating that these streams have greater resource availability or that species can use these resources more efficiently. Our results demonstrate the importance of riparian vegetation for the studied communities, as well as for mitigating the impacts caused by mining activities.

Dynamic Organization of Neuronal Extracellular Matrix Revealed by HaloTag-HAPLN1.

The brain's extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows a net-like structure around a subset of neurons, a ring-like structure at the nodes of Ranvier, and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to hyaluronan proteoglycan link protein 1, which links hyaluronan and proteoglycans. Expression or application of the probe in primary rat neuronal cultures enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in mouse brains of either sex reveals detailed ECM architectures around excitatory neurons and developmentally regulated dendritic ECM. Our study uncovers extensive structural features of the brain's ECM, suggesting diverse roles in regulating neuronal plasticity.

Monoaminergic Modulation of Learning and Cognitive Function in the Prefrontal Cortex.

Extensive research has shed light on the cellular and functional underpinnings of higher cognition as influenced by the prefrontal cortex. Neurotransmitters act as key regulatory molecules within the PFC to assist with synchronizing cognitive state and arousal levels. The monoamine family of neurotransmitters, including dopamine, serotonin, and norepinephrine, play multifaceted roles in the cognitive processes behind learning and memory. The present review explores the organization and signaling patterns of monoamines within the PFC, as well as elucidates the numerous roles played by monoamines in learning and higher cognitive function.

Collaborative activities and flexible working

Digitalization and globalization have radically affected work organization and interaction between workers in the course of performing job duties. Co-creation activity on digital labour platforms is a new phenomenon that has been little studied. The paper aims to explore collaboration as a driving force in the evolution of work organization patterns and investigates its main effects on the labour market. Theory of cooperation and organizational theory constitute the methodological basis of the study. The research methods used are evolutionary analysis, statistical and regression analysis. The empirical evidence is comprised of open data from the European Social Survey (ESS) Round 10 (2020/23). The study identifies the directions for altering the forms of collaborative activities: the key ones are associated with the enhancement of individual value, accumulation of human capital and a rise in worker autonomy. It is shown that organization of work, which is also undergoing significant changes, promotes flexible working practices. The empirical analysis indicates that high-frequency Internet use among self-employed workers significantly increases the probability of engaging in co-creation activities, particularly as education levels rise. The growing intrinsic motivation of participants to such activities leads to higher labour productivity. The findings highlight a critical issue regarding the lack of human resource management practices in platform employment. Designing a new (flexible) model of work organization aligned with the characteristics and effects of co-creation activities can serve as a promising direction for further research.

Programming DNA Nanoassemblies into Polyvalent Lysosomal Degraders for Potent Degradation of Pathogenic Membrane Proteins.

Lysosome-targeting chimera (LYTAC) shows great promise for protein-based therapeutics by targeted degradation of disease-associated membrane or extracellular proteins, yet its efficiency is constrained by the limited binding affinity between LYTAC reagents and designated proteins. Here, we established a programmable and multivalent LYTAC system by tandem assembly of DNA into a high-affinity protein degrader, a heterodimer aptamer nanostructure targeting both pathogenic membrane protein and lysosome-targeting receptor (insulin-like growth factor 2 receptor, IGF2R) with adjustable spatial distribution or organization pattern. The DNA-based multivalent LYTACs showed enhanced efficacy in removing immune-checkpoint protein programmable death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) in tumor cell membrane that respectively motivated a significant increase in T cell activity and a potent effect on cancer cell growth inhibition. With high programmability and versatility, this multivalent LYTAC system holds considerable promise for realizing protein therapeutics with enhanced activity.

Spatial organisation of the soil macrofauna community of an oak forest in the steppe zone of Ukraine

Background. Environmental impact assessments and the development of measures for the protection and sustainable use of ecosystems should take into account that not only steppe ecosystems but also forest, marsh, salt marsh and meadow ecosystems are referenced for the steppe zone. A comparative approach requires the study of reference ecosystems to understand how much a particular ecosystem has been transformed or how far it is from natural patterns in the restoration process. The soil macrofaunal community of the forest ecosystem of the right bank of the Samara River can be considered a reference for many forest ecosystems in the region. The aim of this study was to identify patterns of spatial organization of the soil macrofaunal community of an oak forest on the right bank of the Samara River. Materials and Methods. A study was conducted in a deciduous woodland located in an oak forest on the right bank of the Samara River. The study area was divided into 5 transects, each consisting of 20 sampling points with a 2 m distance between rows. The samples of the soil macrofauna were taken from a single block of soil that was 25×25×30 cm deep and removed quickly. Vascular plant species lists were recorded for each 2×2 m subplot. The soil penetration resistance and electrical conductivity were measured. Soil faunal trophic activity was assessed by means of a bait lamina test. Results and Discussion. The spatial structure of the community is complex in terms of hierarchy. The driver of the broad-scale component of spatial variation in the community is the properties of the topsoil, mainly the density of the litter. Vegetation cover forms a broad component of the spatial variation in soil macrofauna. An important factor in structuring ecological space is the location of trees. The pure spatial pattern is represented by broad-, medium-, and fine-scale components. Conclusion. The soil macrofaunal community of an oak forest on the slope of the right bank of a steppe river has a high level of abundance and taxonomic and ecological diversity. The spatial distribution of trees forms a broad-scale component of variation in the soil macrofaunal community, and herbaceous cover forms a medium-scale component. The fine-scale component of community variation is due to neutral factors.

COVID-19 hits care homes: A cross-national study of mortality rates

The COVID-19 outbreak, which most severely impacted older citizens, served as a stress test for residential eldercare facilities. The mortality rates of care home residents varied widely across countries in 2020 before vaccinations became available. Why have some countries been better (or less) able to protect their older citizens in care homes? This article examines the role of specific characteristics of national systems of residential care in enhancing or weakening the capacity of these systems to protect their residents from the pandemic and seeks to draw some lessons for the future. Because the mortality rate in care homes strongly correlates with the overall infection rate within the community, this article adopts an innovative approach to conceptualize and measure the protection capacity of national residential care systems more specifically – that is net of mortality rates within the community. The study makes important contributions to the care policy field. The traditional care regime typology fails to explain cross-national variations in the protective capacity of care homes. Governmental spending on long-term care systems certainly matters for protective capacity but we find that a factor previously neglected by care regime scholars also matters. More specifically, we show that the pattern of staff organization affects protective capacity. Our findings call for a rethinking of care systems in the face of future pandemics.

Cellular processing of beneficial de novo emerging proteins.

Novel proteins can originate de novo from non-coding DNA and contribute to species-specific adaptations. It is challenging to conceive how de novo emerging proteins may integrate pre-existing cellular systems to bring about beneficial traits, given that their sequences are previously unseen by the cell. To address this apparent paradox, we investigated 26 de novo emerging proteins previously associated with growth benefits in yeast. Microscopy revealed that these beneficial emerging proteins preferentially localize to the endoplasmic reticulum (ER). Sequence and structure analyses uncovered a common protein organization among all ER-localizing beneficial emerging proteins, characterized by a short hydrophobic C-terminus immediately preceded by a transmembrane domain. Using genetic and biochemical approaches, we showed that ER localization of beneficial emerging proteins requires the GET and SND pathways, both of which are evolutionarily conserved and known to recognize transmembrane domains to promote post-translational ER insertion. The abundance of ER-localizing beneficial emerging proteins was regulated by conserved proteasome- and vacuole-dependent processes, through mechanisms that appear to be facilitated by the emerging proteins' C-termini. Consequently, we propose that evolutionarily conserved pathways can convergently govern the cellular processing of de novo emerging proteins with unique sequences, likely owing to common underlying protein organization patterns.

Polarization-sensitive optical coherence tomography and scleral collagen fiber orientation in osteogenesis imperfecta

Osteogenesis imperfecta (OI), a rare genetic connective tissue disorder, primarily arises from pathogenic variants affecting the production or structure of collagen type I. In addition to skeletal fragility, individuals with OI may face an increased risk of developing ophthalmic diseases. This association is believed to stem from the widespread presence of collagen type I throughout various parts of the eye. However, the precise consequences of abnormal collagen type I on different ocular tissues remain unknown. Of particular significance is the sclera, where collagen type I is abundant and crucial for maintaining the structural integrity of the eye. Recent research on healthy individuals has uncovered a unique organizational pattern of collagen fibers within the sclera, characterized by fiber arrangement in both circular and radial layers around the optic nerve head. While the precise function of this organizational pattern remains unclear, it is hypothesized to play a role in providing mechanical support to the optic nerve. The objective of this study is to investigate the impact of abnormal collagen type I on the sclera by assessing the fiber organization near the optic nerve head in individuals with OI and comparing them to healthy individuals. Collagen fiber orientation of the sclera was measured using polarization-sensitive optical coherence tomography (PS-OCT), an extension of the conventional OCT that is sensitive to materials that exhibit birefringence (axial changes in light refraction). Birefringence was quantified and used as imaging contrast to extract collagen fiber orientation as well as the thickness of the radially oriented scleral layer. Three individuals with OI, exhibiting different degrees of disease severity, were assessed and analyzed, along with seventeen healthy individuals. Mean values obtained from individuals with OI were descriptively compared to those of the healthy participant group. PS-OCT revealed a similar orientation pattern of scleral collagen fibers around the optic nerve head between OI individuals and healthy individuals. However, two OI participants exhibited reduced mean birefringence of the radially oriented scleral layer compared to the healthy participant group (OI participant 1 oculus dexter et sinister (ODS): 0.34°/μm, OI participant 2: ODS 0.26°/μm, OI participant 3: OD: 0.29°/μm, OS: 0.28°/μm, healthy participants: ODS 0.38 ± 0.05°/μm). The radially oriented scleral layer was thinner in all OI participants although within ±2 standard deviations of the mean observed in healthy individuals (OI participant 1 OD: 101 μm, OS 104 μm, OI participant 2: OD 97 μm, OS 98 μm, OI participant 3: OD: 94 μm, OS 120 μm, healthy participants: OD 122.8 ± 13.6 μm, OS 120.8 ± 15.1 μm). These findings imply abnormalities in collagen organization or composition, underscoring the necessity for additional research to comprehend the ocular phenotype in OI.

Regional patterns of human cortex development correlate with underlying neurobiology.

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8,000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Tracking the Distance to Criticality in Systems with Unknown Noise

Many real-world systems undergo abrupt changes in dynamics as they move across critical points, often with dramatic and irreversible consequences. Much existing theory on identifying the time-series signatures of nearby critical points, such as increased signal variance and slower timescales, is derived from analytically tractable systems, typically considering the case of fixed, low-amplitude noise. However, real-world systems are often corrupted by unknown levels of noise that can distort these temporal signatures. Here we aim to develop noise-robust indicators of the distance to criticality (DTC) for systems affected by dynamical noise in two cases: when the noise amplitude is either fixed or is unknown and variable across recordings. We present a highly comparative approach to this problem that compares the ability of over 7000 candidate time-series features to track the DTC in the vicinity of a supercritical Hopf bifurcation. Our method recapitulates existing theory in the fixed-noise case, highlighting conventional time-series features that accurately track the DTC. But in the variable-noise setting, where these conventional indicators perform poorly, we highlight new types of high-performing time-series features and show that their success is accomplished by capturing the shape of the invariant density (which depends on both the DTC and the noise amplitude) relative to the spread of fast fluctuations (which depends on the noise amplitude). We introduce a new high-performing time-series statistic, the rescaled autodensity (RAD), that combines these two algorithmic components. We then use RAD to provide new evidence that brain regions higher in the visual hierarchy are positioned closer to criticality, supporting existing hypotheses about patterns of brain organization that are not detected using conventional metrics of the DTC. Our results demonstrate how large-scale algorithmic comparison can yield theoretical insights that can motivate new theory and interpretable algorithms for solving important real-world problems. Published by the American Physical Society 2024

The Genetic Architecture of the Human Corpus Callosum and its Subregions.

The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CC's role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined N = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction.

Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

A multidimensional investigation of sleep and biopsychosocial profiles with associated neural signatures.

Sleep is essential for optimal functioning and health. Interconnected to multiple biological, psychological and socio-environmental factors (i.e., biopsychosocial factors), the multidimensional nature of sleep is rarely capitalized on in research. Here, we deployed a data-driven approach to identify sleep-biopsychosocial profiles that linked self-reported sleep patterns to inter-individual variability in health, cognition, and lifestyle factors in 770 healthy young adults. We uncovered five profiles, including two profiles reflecting general psychopathology associated with either reports of general poor sleep or an absence of sleep complaints (i.e., sleep resilience) respectively. The three other profiles were driven by the use of sleep aids and social satisfaction, sleep duration and cognitive performance, and sleep disturbance linked to cognition and mental health. Furthermore, identified sleep-biopsychosocial profiles displayed unique patterns of brain network organization. In particular, somatomotor network connectivity alterations were involved in the relationships between sleep and biopsychosocial factors. These profiles can potentially untangle the interplay between individuals' variability in sleep, health, cognition and lifestyle - equipping research and clinical settings to better support individual's well-being.

Novel organizational patterns of stability phases in a single-species population model: chiral tree, spikes adding-doubling complexification cascade

Novel organizational patterns of stability phases in a single-species population model: chiral tree, spikes adding-doubling complexification cascade

Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers.

Therapeutics targeting tumor endothelial cells (TECs) have been explored for decades, with only suboptimal efficacy achieved, partly due to an insufficient understanding of the TEC heterogeneity across cancer patients. We integrated single-cell RNA-seq data of 575 cancer patients from 19 solid tumor types, comprehensively charting the TEC phenotypic diversities. Our analyses uncovered underappreciated compositional and functional heterogeneity in TECs from a pan-cancer perspective. Two subsets, CXCR4 + tip cells and SELE + veins, represented the prominent angiogenic and proinflammatory phenotypes of TECs, respectively. They exhibited distinct spatial organization patterns, and compared to adjacent non-tumor tissues, tumor tissue showed an increased prevalence of CXCR4 + tip cells, yet with SELE + veins depleted. Such functional and spatial characteristics underlie their differential associations with the response of anti-angiogenic therapies and immunotherapies. Our integrative resources and findings open new avenues to understand and clinically intervene in the tumor vasculature.