Annual review of immunology · 2021
Mar Cabeza-Cabrerizo、Ana Cardoso、Carlos M Minutti 等
Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.
Biomolecules · 2023
Elliot Lopez、Sahil Kamboj、Chang-Chong Chen 等
Ovarian cancer (OC) is a disease of major concern with a survival rate of about 40% at five years. This is attributed to the lack of visible and reliable symptoms during the onset of the disease, which leads over 80% of patients to be diagnosed at advanced stages. This implies that metastatic activity has advanced to the peritoneal cavity. It is associated with both genetic and phenotypic heterogeneity, which considerably increase the risks of relapse and reduce the survival rate. To understand ovarian cancer pathophysiology and strengthen the ability for drug screening, further development of relevant in vitro models that recapitulate the complexity of OC microenvironment and dynamics of OC cell population is required. In this line, the recent advances of tridimensional (3D) cell culture and microfluidics have allowed the development of highly innovative models that could bridge the gap between pathophysiology and mechanistic models for clinical research. This review first describes the pathophysiology of OC before detailing the engineering strategies developed to recapitulate those main biological features.
Cell reports · 2023
Jose Verdezoto Mosquera、Gaëlle Auguste、Doris Wong 等
Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.
Frontiers in Oncology · 2026
Luis Basbus
The paradigm of the Hallmarks of Cancer, updated by Douglas Hanahan in 2022, represents one of the most influential syntheses for understanding the functional capabilities that sustain neoplastic transformation. However, its traditional interpretation, often reductionist and fragmentary, does not capture the non-linear, emergent, and adaptive dynamics of tumor behavior. This review proposes a reinterpretation of the hallmarks through the lens of complexity theory, conceptualizing colorectal cancer (CRC) as a self-organizing, open system operating far from equilibrium. Using an integrative conceptual approach, we map the ten classical hallmarks and the new dimensions proposed in 2022 (phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescence) onto the fundamental properties of complex systems: nonlinearity, emergence, feedback, openness, and historical dependence. We argue that CRC should not be understood as a simple sum of molecular alterations but as a dynamic network of interactions among cells, tissues, and microenvironments where global organization emerges from local rules. This systems-based perspective provides a conceptual foundation for translational models and integrative methodologies in oncology.
Science (New York, N.Y.) · 2019
Thomas M Norman、Max A Horlbeck、Joseph M Replogle 等
How cellular and organismal complexity emerges from combinatorial expression of genes is a central question in biology. High-content phenotyping approaches such as Perturb-seq (single-cell RNA-sequencing pooled CRISPR screens) present an opportunity for exploring such genetic interactions (GIs) at scale. Here, we present an analytical framework for interpreting high-dimensional landscapes of cell states (manifolds) constructed from transcriptional phenotypes. We applied this approach to Perturb-seq profiling of strong GIs mined from a growth-based, gain-of-function GI map. Exploration of this manifold enabled ordering of regulatory pathways, principled classification of GIs (e.g., identifying suppressors), and mechanistic elucidation of synergistic interactions, including an unexpected synergy between CBL and CNN1 driving erythroid differentiation. Finally, we applied recommender system machine learning to predict interactions, facilitating exploration of vastly larger GI manifolds.
Nature genetics · 2025
Aviya Litman、Natalie Sauerwald、LeeAnne Green Snyder 等
Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition. Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort. We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class. Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses.
FEBS Letters · 2026
L. Proietti、P. Beltrao、Alejandra Bruna 等
Large‐scale perturbational approaches have transformed cancer research, enabling systematic identification of tumour‐specific dependencies and therapeutic vulnerabilities. However, many clinically relevant vulnerabilities arise from genetic interactions, including synthetic lethal and buffering relationships, and are shaped by cellular state, lineage and treatment history. Interpreting complex dependency landscapes increasingly relies on advanced computational and AI‐based approaches integrating molecular, phenotypic and contextual information. In this rapidly evolving setting, dedicated forums are needed to connect experimental and computational perspectives. Following the success of the inaugural European Cancer Dependency Map Symposium, the 2nd EuroDepMap was held on 20 November 2025 at Human Technopole in Milan, bringing together leading scientists in functional genomics, genome‐editing screens, disease models and AI‐driven analysis, marking a pivotal moment for the field.
Cancer Research · 2026
Suman Dutta、Debarpan Mitra、Manoranjan Jha 等
Colorectal cancer (CRC) is an emerging challenge, with rising early onset incidence and high mortality among younger individuals. Curative outcomes remain difficult due to its complexity. While chemotherapy and targeted drugs remain standard, immune checkpoint inhibitors (ICI) and engineered CAR-T are advancing as promising therapy options.
Here we report the development of Aryastha BioSolution®, an integrated patient-derived tumor-immune organoid platform designed to predict therapeutic responses in CRC. The mechanistic interface of this platform enables parallel assessment of agents, ICI, and adoptive cell therapies, while capturing patient specific tumor-immune interaction dynamics that underlie treatment sensitivity and resistance.
Patient Derived Tumor Organoids (PDTOs) were established from surgically resected colorectal tumors and maintained in 3D milieu. PDTOs were treated with human equivalent doses of Oxaliplatin and Capecitabine and tumor killing was measured by live/dead staining. PDTOs were also co-cultured with human immune cells (PBMCs or engineered CAR-Ts) for 72 hours. Dynamics of tumor-immune engagement and therapy-induced organoid killing was tracked using time-lapse live imaging. Modulatory effects of ICI and CAR-T and their inflammatory responses were determined 72 hours post-culture by IFN-γ and chemokines levels.
Early passage PDTOs retained the core genomic and phenotypic landscape of parent tumors, including point mutations, copy-number alterations, microsatellite (MSI) profile, as well as viability (Ki67) and histopathology signatures. Evaluation of SOC regimens showed that PDTO sensitivity markedly correlated with clinical treatment outcomes as measured by PET-CT. Co-culture assays showed distinct infiltration and killing trajectories of ICI treated PBMCs and CAR-T, characterized by robust cytolytic activity and close to 50% tumor volume reduction. We identified augmented IFN-γ and proinflammatory chemokines in responder PDTOs. Genomic profile (MSI-H/MMRd, tumor mutational burden, transcriptomic profile) and reactivity of tumor using these functional readouts underscore the mechanism of response and non-response which align with their known clinical trends.
The PDTO platform effectively bridges the translational gap that conventional models fail to overcome. Aryastha BioSolutions® provides a clinically aligned drug-response system that captures the phenotypic diversity of CRC and delineates the biology distinguishing responders from non-responders, enabling rational therapeutic combinations. The platform’s high translatability positions it to strengthen clinical trial design and personalize both standard and emerging immunotherapy approaches.
Suman Dutta, Debarpan Mitra, Manoranjan Jha, Rimi Mukherjee, Juluri Srinivas, Kadambari Dixit, Krishanu Dey, Aswin Pandit, Sindu Pilli, Chandra C. Ghosh, Amjad Hussain, Gnaneswar Atturu, Ram Shankar Upadhayaya, Pradip K Majumder, Biswanath Majumder. Patient derived tumor-immune organoids capture the functional and mechanistic interface in predicting response to standard therapeutics and immunotherapeutics in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7781.
Science (New York, N.Y.) · 2003
Michael Lynch、John S Conery
Complete genomic sequences from diverse phylogenetic lineages reveal notable increases in genome complexity from prokaryotes to multicellular eukaryotes. The changes include gradual increases in gene number, resulting from the retention of duplicate genes, and more abrupt increases in the abundance of spliceosomal introns and mobile genetic elements. We argue that many of these modifications emerged passively in response to the long-term population-size reductions that accompanied increases in organism size. According to this model, much of the restructuring of eukaryotic genomes was initiated by nonadaptive processes, and this in turn provided novel substrates for the secondary evolution of phenotypic complexity by natural selection. The enormous long-term effective population sizes of prokaryotes may impose a substantial barrier to the evolution of complex genomes and morphologies.
Current Computer - Aided Drug Design · 2026
Wei Yue、Liwen Zhang、Jia-Zhi Xu 等
INTRODUCTION
Colorectal Cancer (CRC) is a prevalent gastrointestinal malignancy with complex pathogenesis involving genetic and epigenetic alterations and multi‑pathway dysregulation. Traditional Chinese Medicine (TCM) offers multi-component and multi-target strategies with relatively low toxicity. Despite widespread clinical use of ginseng radix et rhizoma- containing prescriptions, the core herb combinations and their mechanistic underpinnings in CRC remain insufficiently defined due to heterogeneous prescribing patterns and the complexity of multi‑component actions.
METHODS
Data mining and network pharmacology were integrated to analyze ginseng radix et rhizoma‑containing compound prescriptions for CRC across major databases. Herb information was standardized, and frequency statistics, cluster analysis, and Apriori association rules were applied to identify core combinations. Active compounds were screened using oral bioavailability and drug-likeness filters, targets were predicted and curated; CRC targets were collated from multiple resources, intersecting networks were constructed and prioritized, enrichment analyses were performed, and molecular docking was conducted to support mechanistic hypotheses.
RESULTS
The triad of ginseng radix et rhizoma, atractylodis macrocephalae rhizoma, and glycyrrhizae radix et rhizoma emerged as the core combination. Key constituents included quercetin, licochalcone A, kaempferol, atractylenolide I, and ginsenosides Rg3, Rg1, and Rh2. Core targets were EGFR, STAT3, AKT1, TP53, and VEGFA. Enriched pathways included EGFR, MAPK, PI3K-Akt, and PD-1/PD-L1. Docking supported favorable ligand-target binding.
DISCUSSION
These findings suggest that the core triad may exert anti‑CRC effects through coordinated modulation of oncogenic signaling and the tumor microenvironment, providing a rationale to explore it as an adjuvant to chemotherapy, anti-EGFR therapy, and immune checkpoint blockade. The integrative workflow generates testable hypotheses but requires experimental validation and formulation standardization before clinical translation.
CONCLUSION
This work identifies a core herb triad and maps plausible mechanisms in ginsengcontaining prescriptions for CRC. It contributes a mechanistic framework and prioritized targets and constituents to guide future validation and translational studies. It highlights the utility of data mining and network pharmacology for elucidating the mechanisms of TCM.
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AI 辅助短评，基于标题和摘要整理本研究针对RDEB表型高度异质、缺乏可操作分子模型的问题，基于患儿皮肤转录组构建首個功能性机制图谱，结合机器学习推断靶点并重定位药物。其价值在于将疾病回路与炎症、纤维化、肿瘤进展等标志关联，为靶点发现和已批准药物重定位提供系统依据。