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The dynamic immune behavior of primary and metastatic ovarian carcinoma

npj Precision Oncology 2025年第1期9卷 1-12页

作者： Stur, Elaine Peng, Fuduan Teng, Pang-Ning Bayraktar, Emine Hu, Min Corvigno, Sara Brown, David J. Lee, Sanghoon Moore, Kathleen N. Bateman, Nicholas W. Darcy, Kathleen M. Maxwell, George L. P. Conrads, Thomas Sahni, Nidhi Vázquez-García, Ignacio Shah, Sohrab P. Celestino, Joseph D. Fleming, Nicole Navin, Nicholas E. Wang, Linghua Sood, Anil K. Department of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center Houston TX United States Department of Genomic Medicine The University of Texas MD Anderson Cancer Center Houston TX United States Gynecologic Cancer Center of Excellence The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Walter Reed National Military Medical Center Bethesda 20889 MD United States Department of Gynecologic Surgery and Obstetrics Uniformed Services University of the Health Sciences Walter Reed National Military Medical Center Bethesda MD United States Department of Genetics The University of Texas MD Anderson Cancer Center Houston TX United States Obstetrics and Gynecology Stephenson Cancer Center Stephenson Cancer Center at the University of Oklahoma Health Sciences Center/Sarah Cannon Research Institute Oklahoma City OK United States Women’s Health Integrated Research Center Women’s Service Line Inova Health System Falls Church VA United States Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center Baylor College of Medicine Houston TX United States Department of Bioinformatics and Computational Biology The University of Texas MD Anderson Cancer Center Houston TX United States Quantitative and Computational Biosciences Program Baylor College of Medicine Houston TX United States Computational Oncology Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States The Halvorsen Center for Computational Oncology Memorial Sloan Kettering Cancer Center Boston MA United States Irving Institute for Cancer Dynamics Columbia University Cambridge 10027 MA United States Department of Systems Biology The University of Texas MD Anderson Cancer Center Houston MA United States The James P. Allison Institute The University of Texas MD Anderson Cancer Center Houston 77030 TX United States The Institute for Data Sc

Patients with high-grade serous ovarian carcinoma (HGSC) are usually diagnosed with advanced-stage disease, and the tumors often have immunosuppressive characteristics. Together, these factors are important for disease progression, drug resistance, and mortality. In this study, we used a combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, we found that untreated primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation;this, in turn, was correlated with expression changes in the interferon α and γ pathways in epithelial cells, showing that cross-communication between the epithelial and immune compartments is important for immune suppression in HGSC. These findings could have implications for the design of clinical trials with immune-modulating drugs. © The Author(s) 2025.

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IL-10 from tumoral B cells modulates the diffuse large B-cell lymphoma microenvironment and response to immunotherapy

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Blood 2025年 blood2024025755页

作者： Garcia-Lacarte, Marcos Grijalba, Sara C. Melchor, Javier Pascual, Marién Goñi, Enrique Clemente-Larramendi, Iñigo Morales-Sánchez, Sandra Burrell, María A. Blanco, Oscar Arnaiz-Leché, Adrián Berrozpe, Blanca S. Amann, Maria Klein, Christian Umaña, Pablo Canales, Miguel Martínez-Climent, José Ángel Lasarte, Juan J. Sarobe, Pablo Novo, Francisco J. Roa, Sergio Department of Biochemistry and Genetics Universidad de Navarra Pamplona Spain Cancer Center Clínica Universidad de Navarra Pamplona Spain Navarra Institute for Health Research Pamplona Spain Hemato-Oncology Program Cima Universidad de Navarra Pamplona Spain Computational Biology Program Cima Universidad de Navarra Pamplona Spain Department of Pathology Anatomy and Physiology Universidad de Navarra Pamplona Spain Department of Pathology Hospital Universitario de Salamanca Salamanca Spain Roche Pharma Research and Early Development Roche Innovation Center Zurich Schlieren Switzerland Department of Hematology Clínica Universidad de Navarra Pamplona Spain Centro de Investigación Biomédica en Red de Cáncer Instituto de Salud Carlos III Madrid Spain Immunology and Immunotherapy Program Cima Universidad de Navarra Pamplona Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Instituto de Salud Carlos III Madrid Spain

The contribution of interleukin-10 (IL-10), secreted by tumoral B cells, to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell–like (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knockout of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T-cell depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10–deficient lymphomas acquire a highly immunosuppressed and T-cell–exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, which is refractory to PD-1 immune checkpoint blockade. However, the response of IL-10–deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes the survival of malignant B cells, whereas the paracrine action of B-cell–derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies targeting the lymphoma microenvironment. Furthermore, IL-10–associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Thus, our work provides important functional and mechanistic insights into the role of B-cell–derived IL-10 in the biology of ABC-DLBCL. © 2025 American Society of Hematology

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Rewriting regulatory DNA to dissect and reprogram gene expression

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Cell 2025年

作者： Martyn, Gabriella E. Montgomery, Michael T. Jones, Hank Guo, Katherine Doughty, Benjamin R. Linder, Johannes Bisht, Deepa Xia, Fan Cai, Xiangmeng S. Chen, Ziwei Cochran, Kelly Lawrence, Kathryn A. Munson, Glen Pampari, Anusri Fulco, Charles P. Sahni, Nidhi Kelley, David R. Lander, Eric S. Kundaje, Anshul Engreitz, Jesse M. Department of Genetics Stanford University School of Medicine Stanford 94305 CA United States Basic Science and Engineering Initiative Stanford Children's Health Betty Irene Moore Children's Heart Center Stanford 94305 CA United States Calico Life Sciences LLC South San Francisco 94080 CA United States Department of Genitourinary Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston 77030 TX United States Department of Genomic Medicine The University of Texas MD Anderson Cancer Center Houston 77030 TX United States Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center Houston 77230 TX United States Department of Bioengineering Stanford University Stanford 94305 CA United States Department of Computer Science Stanford University Stanford 94305 CA United States Novo Nordisk Foundation Center for Genomic Mechanisms of Disease Broad Institute of MIT and Harvard Cambridge 02142 MA United States Gene Regulation Observatory Broad Institute of MIT and Harvard Cambridge 02142 MA United States Broad Institute of MIT and Harvard Cambridge 02142 MA United States Department of Bioinformatics and Computational Biology The University of Texas MD Anderson Cancer Center Houston 77230 TX United States Quantitative and Computational Biosciences Program Baylor College of Medicine Houston 77030 TX United States Department of Biology MIT Cambridge 02139 MA United States Department of Systems Biology Harvard Medical School Boston 02115 MA United States Stanford Cardiovascular Institute Stanford University Stanford 94305 CA United States

Regulatory DNA provides a platform for transcription factor binding to encode cell-type-specific patterns of gene expression. However, the effects and programmability of regulatory DNA sequences remain difficult to map or predict. Here, we develop variant effects from flow-sorting experiments with CRISPR targeting screens (Variant-EFFECTS) to introduce hundreds of designed edits to endogenous regulatory DNA and quantify their effects on gene expression. We systematically dissect and reprogram 3 regulatory elements for 2 genes in 2 cell types. These data reveal endogenous binding sites with effects specific to genomic context, transcription factor motifs with cell-type-specific activities, and limitations of computational models for predicting the effect sizes of variants. We identify small edits that can tune gene expression over a large dynamic range, suggesting new possibilities for prime-editing-based therapeutics targeting regulatory DNA. Variant-EFFECTS provides a generalizable tool to dissect regulatory DNA and to identify genome editing reagents that tune gene expression in an endogenous context. © 2025 Elsevier Inc.

关键词： CRISPR enhancers gene regulation high-throughput screening non-coding variants predictive models prime editing RNA FlowFISH sequence design transcription factors

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Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity

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Molecular Cell 2025年

作者： Tigist Y. Tamir Shreya Chaudhary Annie X. Li Sonia E. Trojan Cameron T. Flower Paula Vo Yufei Cui Jeffrey C. Davis Rachit Mukkamala Francesca N. Venditti Alissandra L. Hillis Alex Toker Matthew G. Vander Heiden Jessica B. Spinelli Norman J. Kennedy Roger J. Davis Forest M. White Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA USA Center for Precision Cancer Medicine Massachusetts Institute of Technology Cambridge MA USA Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA USA Department of Biology Massachusetts Institute of Technology Cambridge MA USA Faculty of Medicine Chair of Medical Biochemistry Jagiellonian University Medical College Krakow Poland Program in Computational and Systems Biology Massachusetts Institute of Technology Cambridge MA USA Program in Molecular Medicine University of Massachusetts Chan Medical School Worcester MA USA Department of Pathology and Cancer Center Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA Dana-Farber Cancer Institute Boston MA USA

Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.

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SPATIAL ATTENTION KINETIC NETWORK WITH E(N)-EQUIVARIANCE 11

SPATIAL ATTENTION KINETIC NETWORK WITH E(N)-EQUIVARIANCE

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11th International Conference on Learning Representations, ICLR 2023

作者： Wang, Yuanqing Chodera, John D. Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Ph.D. Program in Physiology Biophysics and System Biology Weill Cornell Medical College Cornell Univerisity New YorkNY10065 United States

Neural networks that are equivariant to rotations, translations, reflections, and permutations on n-dimensional geometric space have shown promise in physical modeling-from modeling potential energy surfaces to forecasting the time evolution of dynamical systems. Current state-of-the-art methods employ spherical harmonics to encode higher-order interactions among particles, which are computationally expensive. In this paper, we propose a simple alternative functional form that uses neurally parametrized linear combinations of edge vectors to achieve equivariance while still universally approximating node environments. Incorporating this insight, we design spatial attention kinetic networks with E(n)-equivariance, or SAKE, which are competitive in many-body system modeling tasks while being significantly faster. © 2023 11th International Conference on Learning Representations, ICLR 2023. All rights reserved.

关键词： Dynamical systems

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Wasserstein Wormhole: Scalable Optimal Transport Distance with Transformer 41

Wasserstein Wormhole: Scalable Optimal Transport Distance wi...

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41st International Conference on Machine Learning, ICML 2024

作者： Haviv, Doron Kunes, Russell Zhang Dougherty, Thomas Burdziak, Cassandra Nawy, Tal Gilbert, Anna Pe'Er, Dana Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center United States Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medicine United States Department of Statistics Columbia University United States Department of Mathematics and Statistics Yale University United States Howard Hughes Medical Institute United States

Optimal transport (OT) and the related Wasserstein metric (W) are powerful and ubiquitous tools for comparing distributions. However, computing pairwise Wasserstein distances rapidly becomes intractable as cohort size grows. An attractive alternative would be to find an embedding space in which pairwise Euclidean distances map to OT distances, akin to standard multidimensional scaling (MDS). We present Wasserstein Wormhole, a transformer-based autoencoder that embeds empirical distributions into a latent space wherein Euclidean distances approximate OT distances. Extending MDS theory, we show that our objective function implies a bound on the error incurred when embedding non-Euclidean distances. Empirically, distances between Wormhole embeddings closely match Wasserstein distances, enabling linear time computation of OT distances. Along with an encoder that maps distributions to embeddings, Wasserstein Wormhole includes a decoder that maps embeddings back to distributions, allowing for operations in the embedding space to generalize to OT spaces, such as Wasserstein barycenter estimation and OT interpolation. By lending scalability and interpretability to OT approaches, Wasserstein Wormhole unlocks new avenues for data analysis in the fields of computational geometry and single-cell biology. Software is available at http://***/en/latest/. Copyright 2024 by the author(s)

关键词： Embeddings

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KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma

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Nature Communications 2025年第1期16卷 1-20页

作者： Mihalas, Anca B. Arora, Sonali O’Connor, Samantha A. Feldman, Heather M. Cucinotta, Christine E. Mitchell, Kelly Bassett, John Kim, Dayoung Jin, Kang Hoellerbauer, Pia Delegard, Jennifer Ling, Melissa Jenkins, Wesley Kufeld, Megan Corrin, Philip Carter, Lucas Tsukiyama, Toshio Aronow, Bruce Plaisier, Christopher L. Patel, Anoop P. Paddison, Patrick J. Human Biology Division Fred Hutchinson Cancer Center Seattle 98109 WA United States School of Biological and Health Systems Engineering Arizona State University Tempe 85281 AZ United States College of Arts and Sciences Department of Molecular Genetics Ohio State University Columbus 43210 OH United States Basic Sciences Division Fred Hutchinson Cancer Center Seattle 98109 WA United States Department of Medicine Karolinska Institute Huddinge Sweden Division of Biomedical Informatics Cincinnati Children’s Hospital Medical Center Cincinnati 45229 OH United States Department of Neurosurgery University of Washington Seattle 98195 WA United States Molecular and Cellular Biology Program University of Washington Seattle 98195 WA United States Department of Neurosurgery Duke University Durham 27710 NC United States Preston Robert Tisch Brain Tumor Center Duke University Durham 27710 NC United States Center for Advanced Genomic Technologies Duke University Durham 27710 NC United States

Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas. © The Author(s) 2025.

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Opposing Evolutionary Pressures Drive Clonal Evolution and Health Outcomes in the Aging Blood System

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BLOOD 2020年 136卷 37-37页

作者： Skead, Kimberly Houle, Armande Ang Abelson, Sagi Fave, Marie-Julie Lin, Boxi Soave, David Wright, Stephen Dick, John E. Morris, Quaid Awadalla, Phillip Department of Molecular Genetics University of Toronto Toronto Canada Ontario Institute for Cancer Research Toronto Canada Dalla Lana School of Public Health University of Toronto Toronto Canada Department of Mathematics Wilfrid Laurier Univesity Waterloo Canada Department of Ecology and Evolutionary Biology University of Toronto Toronto Canada Princess Margaret Cancer Centre University Health Network (UHN) Toronto Canada Computational & Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY

The age-associated accumulation of somatic mutations and large-scale structural variants (SVs) in the early hematopoietic hierarchy have been linked to premalignant stages for cancer and cardiovascular disease (CVD). However, only a small proportion of individuals harboring these mutations progress to disease, and mechanisms driving the transformation to malignancy remains unclear. Hematopoietic evolution, and cancer evolution more broadly, has largely been studied through a lens of adaptive evolution and the contribution of functionally neutral or mildly damaging mutations to early disease-associated clonal expansions has not been well characterised despite comprising the majority of the mutational burden in healthy or tumoural tissues. Through combining deep learning with population genetics, we interrogate the hematopoietic system to capture signatures of selection acting in healthy and pre-cancerous blood populations. Here, we leverage high-coverage sequencing data from healthy and pre-cancerous individuals from the European Prospective Investigation into cancer and Nutrition Study (n=477) and dense genotyping from the Canadian Partnership for Tomorrow's Health (n=5,000) to show that blood rejects the paradigm of strictly adaptive or neutral evolution and is subject to pervasive negative selection. We observe clear age associations across hematopoietic populations and the dominant class of selection driving evolutionary dynamics acting at an individual level. We find that both the location and ratio of passenger to driver mutations are critical in determining if positive selection acting on driver mutations is able to overwhelm regulated hematopoiesis and allow clones harbouring disease-predisposing mutations to rise to dominance. Certain genes are enriched for passenger mutations in healthy individuals fitting purifying models of evolution, suggesting that the presence of passenger mutations in a subset of genes might confer a protective role against disease-pr

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Lineage plasticity in cancer: a shared pathway of therapeutic resistance (Mar, 10.1038/s41571-020-0340-z, 2020)

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NATURE REVIEWS CLINICAL ONCOLOGY 2020年第6期17卷 382-382页

作者： Quintanal-Villalonga, Alvaro Chan, Joseph M. Yu, Helena A. Pe'er, Dana Sawyers, Charles L. Sen, Triparna Rudin, Charles M. Department of Medicine Thoracic Oncology Service Memorial Sloan Kettering Cancer Center New York NY USA Program for Computational and Systems Biology Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA

Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer — the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives — was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.

关键词： Epithelial–mesenchymal transition Mechanisms of disease Prostate cancer Small-cell lung cancer

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FOXA2 promotes metastatic competence in small cell lung cancer

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Nature communications 2025年第1期16卷 4865页

作者： Kenta Kawasaki Sohrab Salehi Yingqian A Zhan Kevin Chen Jun Ho Lee Eralda Salataj Hong Zhong Parvathy Manoj Dennis Kinyua Barbara P Mello Harsha Sridhar Sam E Tischfield Irina Linkov Nicholas Ceglia Matthew Zatzman Eliyahu Havasov Neil J Shah Fanli Meng Brian Loomis Umesh K Bhanot Esther Redin Elisa de Stanchina Pierre-Jacques Hamard Richard P Koche Andrew McPherson Álvaro Quintanal-Villalonga Sohrab P Shah Joan Massagué Charles M Rudin Cancer Biology and Genetics Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Computational Oncology Program Memorial Sloan Kettering Cancer Center New York NY USA. Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY USA. Antitumor Assessment Core Memorial Sloan Kettering Cancer Center New York NY USA. Marie-Josée and Henry R. Kravis Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY USA. Pathology Core Facility Memorial Sloan Kettering Cancer Center New York NY USA. Cancer Biology and Genetics Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. massaguj@***. Weill Cornell Medicine Graduate School of Medical Sciences New York NY USA. massaguj@***. Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. rudinc@***. Weill Cornell Medicine Graduate School of Medical Sciences New York NY USA. rudinc@***.

Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compare gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identifies FOXA2 as a transcription factor strongly associated with SCLC metastasis. Subsequent analyses in experimental models demonstrates that FOXA2 induces a fetal neuroendocrine gene expression program and promotes multi-site metastasis. Moreover, we identify ASCL1, a transcription factor known for its initiating role in SCLC tumorigenesis, as a direct binder of the FOXA2 promoter and regulator of FOXA2 expression. Taken together, these data define the ASCL1-FOXA2 axis as a critical driver of multiorgan SCLC metastasis.

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