Complex Communication Networks Research Articles

MicroNet-MIMRF: A Microbial Network Inference Approach Based on Mutual Information and Markov Random Fields

Abstract Motivation The human microbiome, comprises complex associations and communication networks among microbial communities, which are crucial for maintaining health. The construction of microbial networks is vital for elucidating these associations and co-occurrence patterns. However, existing microbial networks inference methods cannot solve the issues of zero-inflation and non-linear associations. Therefore, necessitating novel methods to improve the accuracy of microbial networks inference. Results In this study, we introduce the Microbial Network based on Mutual Information and Markov Random Fields (MicroNet-MIMRF) as a novel approach for inferring microbial networks. Abundance data of microbes are modeled through the zero-inflated Poisson distribution, and the discrete matrix is estimated for further calculation. Markov random fields based on mutual information are used to construct accurate microbial networks. MicroNet-MIMRF excels at estimating pairwise associations between microbes, effectively addressing zero-inflation and non-linear associations in microbial abundance data. It outperforms commonly used techniques in simulation experiments, achieving area under the curve values exceeding 0.75 for all parameters. A case study on inflammatory bowel disease data further demonstrates the method’s ability to identify insightful associations. Conclusively, MicroNet-MIMRF is a powerful tool for microbial network inference that handles the biases caused by zero-inflation and overestimation of associations. This novel tool has abundant applications in health research. Availability and implementation The MicroNet-MIMRF is provided at https://github.com/Fionabiostats/MicroNet-MIMRF.

Transnational Cyber Governance for Risk Management in the Gas Sector: Exploring the Potential of G7 Cooperation

At the Group of Seven (G7) summit held on 13–15 June in 2024, the Group’s leaders committed to establishing a collective cyber security framework and reinforcing the work of the cyber security working group to manage the risks targeting energy systems. Likewise, oil and electricity, and natural gas rely on complex and interdependent technologies and communication networks from production to consumption. The preparedness to handle cyber security threats in the energy infrastructures among decision makers, planners, and the industry in a concerted manner signifies that cyber security is becoming more appreciated. Therefore, considering the ambition and achievement of the G7 countries towards energy and cyber sovereignty, this paper’s focus and research question aims to explore the potential existence of the cyber governance alliance in the gas subsector within the G7. The objective of this paper is twofold. First, it explores the potential of the G7, the world’s seven largest advanced economies, to lead on a nascent cyber governance for risk management in the gas sector. The qualitative analysis conducted through the institutional analysis and design method examines up-to-date data involving mainly state actors. Second, by drawing on LNG, one of the world’s fastest growing energy types in the coming decades, the paper points out the need for further research on the transnational governance operating through public–private engagement to address the cyber risks to gas systems. While the paper makes an empirical contribution to the field of security governance and a practical contribution to security consulting, its limitations rely on the necessity to also conduct a quantitative enquiry, which would necessitate, among others, a review of the literature in the G7 countries, and a group of researchers from academia and practitioners to obtain a sense of the cyberspace in the energy reality.

Geospatial Mapping and Meteorological Flood Risk Assessment: A Global Research Trend Analysis.

Flooding is a global threat causing significant economic and environmental damage, necessitating a policy response and collaborative strategy. This study assessed global research trends and advances in geospatial and meteorological flood risk assessment (G_MFRA), considering the ongoing debate on flood risk management and adaptation strategies. A total of 1872 original articles were downloaded in BibTex format using the Web of Science (WOS) and Scopus databases to retrieve G_MFRA studies published from 1985 to 2023. The annual growth rate of 15.48% implies that the field of G_MFRA has been increasing over time during the study period. The analysis of global trends in flood risk research and practice highlights the key themes, methodologies, and emerging directions. There exists a notable gap in data and methodologies for flood risk assessment studies between developed and developing countries, particularly in Africa and South America, highlighting the urgency of coordinated research efforts and cohesive policy actions. The challenges identified in the body of extant literature include technical expertise, complex communication networks, and resource constraints associated with the application gaps of the study methodologies. This study advocates for a holistic research approach to flood disaster management through ecosystem-based adaptation that underpins the Sustainable Development Goals to develop innovative flood techniques and models with the potential to influence global decision-making in the G_MFRA domain. Addressing these global challenges requires a networked partnership between the research community, institutions, and countries.

Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders.

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.

CellChat for systematic analysis of cell-cell communication from single-cell transcriptomics.

Recent advances in single-cell sequencing technologies offer an opportunity to explore cell-cell communication in tissues systematically and with reduced bias. A key challenge is integrating known molecular interactions and measurements into a framework to identify and analyze complex cell-cell communication networks. Previously, we developed a computational tool, named CellChat, that infers and analyzes cell-cell communication networks from single-cell transcriptomic data within an easily interpretable framework. CellChat quantifies the signaling communication probability between two cell groups using a simplified mass-action-based model, which incorporates the core interaction between ligands and receptors with multisubunit structure along with modulation by cofactors. Importantly, CellChat performs a systematic and comparative analysis of cell-cell communication using a variety of quantitative metrics and machine-learning approaches. CellChat v2 is an updated version that includes additional comparison functionalities, an expanded database of ligand-receptor pairs along with rich functional annotations, and an Interactive CellChat Explorer. Here we provide a step-by-step protocol for using CellChat v2 on single-cell transcriptomic data, including inference and analysis of cell-cell communication from one dataset and identification of altered intercellular communication, signals and cell populations from different datasets across biological conditions. The R implementation of CellChat v2 toolkit and its tutorials together with the graphic outputs are available at https://github.com/jinworks/CellChat . This protocol typically takes ~5 min depending on dataset size and requires a basic understanding of R and single-cell data analysis but no specialized bioinformatics training for its implementation.

Single-cell atlas of healthy vocal folds and cellular function in the endothelial-to-mesenchymal transition.

The vocal fold is an architecturally complex organ comprising a heterogeneous mixture of various layers of individual epithelial and mesenchymal cell lineages. Here we performed single-cell RNA sequencing profiling of 5836 cells from the vocal folds of adult Sprague-Dawley rats. Combined with immunostaining, we generated a spatial and transcriptional map of the vocal fold cells and characterized the subpopulations of epithelial cells, mesenchymal cells, endothelial cells, and immune cells. We also identified a novel epithelial-to-mesenchymal transition-associated epithelial cell subset that was mainly found in the basal epithelial layers. We further confirmed that this subset acts as intermediate cells with similar genetic features to epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. Finally, we present the complex intracellular communication network involved homeostasis using CellChat analysis. These studies define the cellular and molecular framework of the biology and pathology of the VF mucosa and reveal the functional importance of developmental pathways in pathological states in cancer.

Dissection of the cell communication interactions in lung adenocarcinoma identified a prognostic model with immunotherapy efficacy assessment and a potential therapeutic candidate gene ITGB1

BackgroundThe tumor microenvironment (TME) in lung adenocarcinoma (LUAD) influences tumor progression and immunosuppressive phenotypes through cell communication. We aimed to decipher cellular communication and molecular patterns in LUAD. MethodsWe analyzed scRNA-seq data from LUAD patients in multiple cohorts, revealing complex cell communication networks within the TME. Using cell chat analysis and COSmap technology, we inferred LUAD's spatial organization. Employing the NMF algorithm and survival screening, we identified a cell communication interactions (CCIs) model and validated it across various datasets. ResultsWe uncovered intricate cell communication interactions within the TME, identifying three LUAD patient subtypes with distinct prognosis, clinical characteristics, mutation status, expression patterns, and immune infiltration. Our CCI model exhibited robust performance in prognosis and immunotherapy response prediction. Several potential therapeutic targets and agents for high CCI score patients with immunosuppressive profiles were identified. Machine learning algorithms pinpointed the novel candidate gene ITGB1 and validated its role in LUAD tumor phenotype in vitro. ConclusionOur study elucidates molecular patterns and cell communication interactions in LUAD as effective biomarkers and predictors of immunotherapy response. Targeting cell communication interactions offers novel avenues for LUAD immunotherapy and prognostic evaluations, with ITGB1 emerging as a promising therapeutic target.

Integrative analysis of single-Cell RNA sequencing and experimental validation in the study of abdominal aortic aneurysm progression

BackgroundAbdominal aortic aneurysm (AAA) is a complex vascular disorder characterized by the progressive dilation of the abdominal aorta, with a high risk of rupture and mortality.Understanding the cellular interactions and molecular mechanisms underlying AAA development is critical for identifying potential therapeutic targets. MethodsThis study utilized datasets GSE197748, GSE164678 and GSE183464 from the GEO database, encompassing bulk and single-cell RNA sequencing data from AAA and control samples. We performed principal component analysis, differential expression analysis, and functional enrichment analysis to identify key pathways involved in AAA. Cell-cell interactions were investigated using CellPhoneDB, focusing on fibroblasts, vascular smooth muscle cells (VSMCs), and macrophages. We further validated our findings using a mouse model of AAA induced by porcine pancreatic enzyme infusion, followed by gene expression analysis and co-immunoprecipitation experiments. ResultsOur analysis revealed significant alterations in gene expression profiles between AAA and control samples, with a pronounced immune response and cell adhesion pathways being implicated. Single-cell RNA sequencing data highlighted an increased proportion of pro-inflammatory macrophages, along with changes in the composition of fibroblasts and VSMCs in AAA. CellPhoneDB analysis identified critical ligand-receptor interactions, notably collagen type I alpha 1 chain (COL1A1)/COL1A2-CD18 and thrombospondin 1 (THBS1)-CD3, suggesting complex communication networks between fibroblasts and VSMCs. In vivo experiments confirmed the upregulation of these genes in AAA mice and demonstrated the functional interaction between COL1A1/COL1A2 and CD18. ConclusionThe interaction between fibroblasts and VSMCs, mediated by specific ligand-receptor pairs such as COL1A1/COL1A2-CD18 and THBS1-CD3, plays a pivotal role in AAA pathogenesis.

Multitrophic and Multilevel Interactions Mediated by Volatile Organic Compounds.

Plants communicate with insects and other organisms through the release of volatile organic compounds (VOCs). Using Boolean operators, we retrieved 1093 articles from the Web of Science and Scopus databases, selecting 406 for detailed analysis, with approximately 50% focusing on herbivore-induced plant volatiles (HIPVs). This review examines the roles of VOCs in direct and indirect plant defense mechanisms and their influence on complex communication networks within ecosystems. Our research reveals significant functions of VOCs in four principal areas: activating insect antennae, attracting adult insects, attracting female insects, and attracting natural enemies. Terpenoids like α-pinene and β-myrcene significantly alter pest behavior by attracting natural enemies. β-ocimene and β-caryophyllene are crucial in regulating aboveground and belowground interactions. We emphasize the potential applications of VOCs in agriculture for developing novel pest control strategies and enhancing crop resilience. Additionally, we identify research gaps and propose new directions, stressing the importance of comparative studies across ecosystems and long-term observational research to better understand VOCs dynamics. In conclusion, we provide insights into the multifunctionality of VOCs in natural ecosystems, their potential for future research and applications, and their role in advancing sustainable agricultural and ecological practices, contributing to a deeper understanding of their mechanisms and ecological functions.

Optimization of the Colony Size Parameter in the Ant Algorithm for Solving the Routing Problem in Communication Networks

With the increasing amount of information and complexity of communication networks, the issue of routing remains relevant. The routing problem is a classic problem of building a logical structure of a communication network. To solve this problem, many methods are used, such as: genetic algorithms, ant algorithm, swarm intelligence, artificial bee colony algorithm, firefly algorithm, bacterial food search optimization algorithm, etc. Despite the fact that the effectiveness of using the ant algorithm is widely known and described, however, there is no single approach to finding the optimal use case for the algorithm. There is a need to determine the optimal size of the colony when solving the routing problem. The article describes the results of the simulation process of modeling the behavior of ant colonies of different sizes to find the optimal route through the AnyLogic environment. It is determined that by means of simulation it is possible to reproduce the use of the ant algorithm to solve the routing problem in communication networks. To find the optimal ratio of the colony size to the complexity of the task, you can use the grid search methodology. The results clearly demonstrate that with increasing complexity of the task (the number of communication nodes), the same number of ants cope worse with the task. The problem associated with the need to accurately determine the optimal size of a colony is of great practical importance, because an increase in the size of a colony has generally decreasing utility. It was found that for many, an increase in the number of ants from 100 to 500 had a relatively greater effect than an increase in the size of the colony from 1000 to 10000. It is proved that by means of simulation it is possible to reproduce the use of the ant algorithm to solve the routing problem in communication networks.

Enhancing Brain Elasticity: Key Lifestyle Habits to Unlock Genius Potential at Any Age

The brain is a masterpiece, often referred to as the king organ, as it governs the entire body. When the brain ceases to function, it marks the end of an individual's vitality, essentially rendering them a "vegetable." This profound importance raises a crucial question: Are we adequately nurturing and caring for our brains? In today's fast-paced world, humans often subject their brains to relentless stress and negative impulses, leading to cognitive decline. However, enhancing brain elasticity can be remarkably simple by adopting specific daily habits. These habits not only pamper the brain but also make it sharper and stronger. Key factors in boosting brain capacity include maintaining optimal hydration, engaging in IQ-enhancing non-digital games like chess and Scrabble, solving logical math problems, regular exercise, and meditation. Additionally, incorporating fruits and vegetables into the diet, consuming foods rich in Omega-3 and DHA, ensuring 8 hours of sleep, reducing screen time, learning new languages, playing various musical instruments, and fostering a positive and resilient mindset are vital. One crucial yet often overlooked habit is regular reading. Reading stimulates the brain, improves concentration, enhances vocabulary, and fosters a deeper understanding of diverse subjects, all of which contribute to increased cognitive flexibility and brain elasticity. Another important factor is maintaining good gut health. Recent research has shown that good gut bacteria play a crucial role in increasing brain activity. The gut-brain axis, a complex communication network, connects the gut and brain, allowing gut bacteria to influence cognitive functions. Probiotics and a diet rich in fiber can enhance the diversity and health of gut microbiota, leading to improved brain function and mental health. This review explores how these lifestyle practices contribute to cognitive enhancement, potentially transforming ordinary individuals into geniuses. It posits that genius is not an inherent trait but a result of deliberate and consistent mental engagement and nurturing. By embracing these strategies, including the habit of regular reading and maintaining good gut health, individuals can significantly elevate their cognitive abilities and achieve exceptional intellectual growth.

Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies.

Triple-negative breast cancer (TNBC)is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME)and breast cancer stem cells (BCSCs)plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs),cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.

New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication.

Cancer is one of the leading causes of death worldwide, and more effective ways of attacking cancer are being sought. Cancer immunotherapy is a new and effective therapeutic method after surgery, radiotherapy, chemotherapy, and targeted therapy. Cancer immunotherapy aims to kill tumor cells by stimulating or rebuilding the body's immune system, with specific efficiency and high safety. However, only few tumor patients respond to immunotherapy and due to the complex and variable characters of cancer immune escape, the behavior and regulatory mechanisms of immune cells need to be deeply explored from more dimensions. Epigenetic modifications, metabolic modulation, and cell-to-cell communication are key factors in immune cell adaptation and response to the complex tumor microenvironment. They collectively determine the state and function of immune cells through modulating gene expression, changing in energy and nutrient demands. In addition, immune cells engage in complex communication networks with other immune components, which are mediated by exosomes, cytokines, and chemokines, and are pivotal in shaping the tumor progression and therapeutic response. Understanding the interactions and combined effects of such multidimensions mechanisms in immune cell modulation is important for revealing the mechanisms of immunotherapy failure and developing new therapeutic targets and strategies.

A nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila

Pancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.

DNA Reaction Circuits to Establish Designated Biological Functions in Multicellular Community.

In multicellular organisms, individual cells are coordinated through complex communication networks to accomplish various physiological tasks. Aiming to establish new biological functions in the multicellular community, we used DNA as the building block to develop a cascade of nongenetic reaction circuits to establish a dynamic cell-cell communication network. Utilizing membrane-anchored amphiphilic DNA tetrahedra (TDN) as the nanoscaffold, reaction circuits were incorporated into three unrelated cells in order to uniquely regulate their sense-and-response behaviors. As a proof-of-concept, this step enabled these cells to simulate significant biological events involved in T cell-mediated anticancer immunity. Such events included cancer-associated antigen recognition and the presentation of antigen-presenting cells (APCs), APC-facilitated T cell activation and dissociation, and T cell-mediated cancer targeting and killing. By combining the excellent programmability and molecular recognition ability of DNA, our cell-surface reaction circuits hold promise for mimicking and manipulating many biological processes.

Single-Cell Informatics for Tumor Microenvironment and Immunotherapy.

Cancer comprises malignant cells surrounded by the tumor microenvironment (TME), a dynamic ecosystem composed of heterogeneous cell populations that exert unique influences on tumor development. The immune community within the TME plays a substantial role in tumorigenesis and tumor evolution. The innate and adaptive immune cells "talk" to the tumor through ligand-receptor interactions and signaling molecules, forming a complex communication network to influence the cellular and molecular basis of cancer. Such intricate intratumoral immune composition and interactions foster the application of immunotherapies, which empower the immune system against cancer to elicit durable long-term responses in cancer patients. Single-cell technologies have allowed for the dissection and characterization of the TME to an unprecedented level, while recent advancements in bioinformatics tools have expanded the horizon and depth of high-dimensional single-cell data analysis. This review will unravel the intertwined networks between malignancy and immunity, explore the utilization of computational tools for a deeper understanding of tumor-immune communications, and discuss the application of these approaches to aid in diagnosis or treatment decision making in the clinical setting, as well as the current challenges faced by the researchers with their potential future improvements.

The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota-Gut-Brain Axis: A Literature Review.

The microbiota-gut-brain (MGB) axis is a complex communication network linking the gut, microbiota, and brain, influencing various aspects of health and disease. Dysbiosis, a disturbance in the gut microbiome equilibrium, can significantly impact the MGB axis, leading to alterations in microbial composition and function. Emerging evidence highlights the connection between microbiota alterations and neurological and psychiatric disorders, including depression. This review explores the potential of psychobiotics in managing depressive disorders, emphasizing their role in restoring microbial balance and influencing the MGB axis. Psychobiotics exhibit positive effects on the intestinal barrier, immune response, cortisol levels, and the hypothalamic-pituitary-adrenal (HPA) axis. Studies suggest that probiotics may serve as an adjunct therapy for depression, especially in treatment-resistant cases. This review discusses key findings from studies on psychobiotics interventions, emphasizing their impact on the gut-brain axis and mental health. The increasing acceptance of the expanded concept of the MGB axis underscores the importance of microorganisms in mental well-being. As our understanding of the microbiome's role in health and disease grows, probiotics emerge as promising agents for addressing mental health issues, providing new avenues for therapeutic interventions in depressive disorders.

Telocytes: current methods of research, challenges and future perspectives.

Telocytes (TCs) are CD34-positive interstitial cells that have long cytoplasmic projections, called telopodes; they have been identified in several organs and in various species. These cells establish a complex communication network between different stromal and epithelial cell types, and there is growing evidence that they play a key role in physiology and pathology. In many tissues, TC network impairment has been implicated in the onset and progression of pathological conditions, which makes the study of TCs of great interest for the development of novel therapies. In this review, we summarise the main methods involved in the characterisation of these cells as well as their inherent difficulties and then discuss the functional assays that are used to uncover the role of TCs in normal and pathological conditions, from the most traditional to the most recent. Furthermore, we provide future perspectives in the study of TCs, especially regarding the establishment of more precise markers, commercial lineages and means for drug delivery and genetic editing that directly target TCs.

Single-cell profiling transcriptomic reveals cellular heterogeneity and cellular crosstalk in choroidal neovascularization model

Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration (nAMD) and a major contributor to vision loss in nAMD cases. However, the identification of specific cell types associated with nAMD remains challenging. Herein, we performed single-cell sequencing to comprehensively explore the cellular diversity and understand the foundational components of the retinal pigment epithelium (RPE)/choroid complex. We unveiled 10 distinct cell types within the RPE/choroid complex. Notably, we observed significant heterogeneity within endothelial cells (ECs), fibroblasts, and macrophages, underscoring the intricate nature of the cellular composition in the RPE/choroid complex. Within the EC category, four distinct clusters were identified and EC cluster 0 was tightly associated with choroidal neovascularization. We identified five clusters of fibroblasts actively involved in the pathogenesis of nAMD, influencing fibrotic responses, angiogenic effects, and photoreceptor function. Additionally, three clusters of macrophages were identified, suggesting their potential roles in regulating the progression of nAMD through immunomodulation and inflammation regulation. Through CellChat analysis, we constructed a complex cell-cell communication network, revealing the role of EC clusters in interacting with fibroblasts and macrophages in the context of nAMD. These interactions were found to govern angiogenic effects, fibrotic responses, and inflammatory processes. In summary, this study reveals noteworthy cellular heterogeneity in the RPE/choroid complex and provides valuable insights into the pathogenesis of CNV. These findings will open up potential avenues for deep understanding and targeted therapeutic interventions in nAMD.

Abstract 5514: Crosstalk between prostatic epithelial cells and the tumor microenvironment drives cancer progression and metastasis

Abstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. Recent advances in the clinical handling of localized prostate cancers resulted in an almost 100% 10-year survival, but no curative treatment is currently available for metastatic disease. Thus, understanding the molecular mechanisms of progression of primary tumors to metastasis is crucial to develop new therapeutic strategies. While tumorigenesis initiates in prostatic epithelial cells, various cell types, including cancer associated fibroblasts (CAFs), immune and endothelial cells produce extra-cellular matrix and secrete signaling molecules that might contribute to tumor progression. However, the complex communication network driving tumor progression is poorly characterized. As the tumor suppressors PTEN and TP53 are among the most frequently altered genes in prostate cancer, we generated genetically engineered mice with Pten and Trp53 selective inactivation in prostatic epithelial cells at adulthood. Their analysis revealed that they develop precancerous lesions that progress to invasive and metastatic tumors. Spatial transcriptomic and single-cell analyses of Pten- and Trp53-deficient prostatic tumors identified the presence of a cancer cell population exhibiting cell plasticity driven by Jak/Stat3 signaling and induced by CAF-produced IL6. In addition, these tumors exhibit a hypoxic core and an immune infiltrate dominated by neutrophils. Inhibition of the hypoxic signaling reduced immune infiltration in primary tumors and their metastatic potential, but did not induce apoptosis of Pten- and Trp53- deficient epithelial cells, in contrast to those of Pten-deficient tumors. These results underline the importance of the tumor genomic background for therapeutic intervention. Taken together, our work highlights the key role of the tumor microenvironment in driving prostate cancer progression and uncovers new vulnerabilities of this disease. Citation Format: Darya Yanushko, Beatriz German Falcon, Céline Keime, Tao Ye, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny. Crosstalk between prostatic epithelial cells and the tumor microenvironment drives cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5514.