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Engineering mtDNA deletions by reconstituting end joining in human mitochondria

Cell 2025年第10期188卷 2778-2793.e21,24页

作者： Fu, Yi Land, Max Kavlashvili, Tamar Cui, Ruobing Kim, Minsoo DeBitetto, Emily Lieber, Toby Ryu, Keun Woo Choi, Elim Masilionis, Ignas Saha, Rahul Takizawa, Meril Baker, Daphne Tigano, Marco Lareau, Caleb A. Reznik, Ed Sharma, Roshan Chaligne, Ronan Thompson, Craig B. Sfeir, Agnel Molecular Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY United States Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY United States Cancer Biology and Genetics Program Memorial Sloan Kettering Cancer Center New York NY United States Computational Oncology Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology and Genomic Medicine Thomas Jefferson University Philadelphia PA United States Howard Hughes Medical Institute New York NY United States

Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies. © 2025 Elsevier Inc.

关键词： DOGMA-seq end joining mitochondrial pathologies mtDNA mtDNA deletion

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The grand biological universe: A comprehensive geometric construction of genome space

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Innovation 2025年

作者： Yu, Hongyu Sun, Nan Ren, Ruohan Zhou, Tao Guan, Mengcen Zhao, Leqi Yau, Stephen S.-T. Department of Mathematical Sciences Tsinghua University Beijing100084 China Beijing101408 China Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medicine New YorkNY10065 United States

Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics. The natural vector method constructs a genome space by extracting statistical moments of k-mers to illuminate the relationships among genomes. This approach highlights a fundamental law in biology known as the convex hull principle, which states that natural vectors corresponding to different types of biological sequences form distinct, non-overlapping convex hulls. Previous studies have validated this important principle across various datasets. However, they often focused on specific kingdoms and did not thoroughly analyze the significance of the dimensions required for the convex hull separation. In this study, we integrate all reliable sequences from different kingdoms to construct the grand biological universe, within which we comprehensively validate the multi-level convex hull principle. We demonstrate that the separation of convex hulls arises from biological properties rather than mathematical characteristics of high-dimensional spaces. Furthermore, we develop suitable metrics within the grand biological universe to facilitate efficient sequence classification. This research advances the convex hull principle through both theoretical development and experimental validation, making significant contributions to the understanding of the geometric structure of genome space. © 2025 The Author(s)

关键词： Hilbert spaces

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy Manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.Mello Metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm Morrsey Sanjoy Mehta Jesse Barnes Michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.Chan Charles M.Rudin Department of Medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of Medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility Memorial Sloan Kettering Cancer Center New YorkNYUSA Department of Laboratory Medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell Medical College New York NYUSA Present address:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological *** overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies (vol 23, pg 904, 2022)

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NATURE IMMUNOLOGY 2022年第8期23卷 1285-1285页

作者： Kansler, Emily R. Dadi, Saida Krishna, Chirag Nixon, Briana G. Stamatiades, Efstathios G. Liu, Ming Kuo, Fengshen Zhang, Jing Zhang, Xian Capistrano, Kristelle Blum, Kyle A. Weiss, Kate Kedl, Ross M. Cui, Guangwei Ikuta, Koichi Chan, Timothy A. Leslie, Christina S. Hakimi, A. Ari Li, Ming O. Immunology Program Memorial Sloan Kettering Cancer Center New York NY USA Louis V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY USA Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA Immunology and Microbial Pathogenesis Graduate Program Weill Cornell Graduate School of Medical Sciences Cornell University New York NY USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA Department of Immunology and Microbiology University of Colorado Anschutz Medical Campus Aurora CO USA Laboratory of Immune Regulation Department of Virus Research Institute for Frontier Life and Medical Sciences Kyoto University Kyoto Japan Department of Urology Memorial Sloan Kettering Cancer Center New York NY USA

Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.

关键词： Immunosurveillance Innate lymphoid cells Biomedicine general Immunology Infectious Diseases

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Directed Scattering for Knowledge Graph-Based Cellular Signaling Analysis

Directed Scattering for Knowledge Graph-Based Cellular Signa...

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International Conference on Acoustics, Speech, and Signal Processing (ICASSP)

作者： Aarthi Venkat Joyce Chew Ferran Cardoso Rodriguez Christopher J. Tape Michael Perlmutter Smita Krishnaswamy Program for Computational Biology and Bioinformatics Yale University Department of Mathematics University of California Los Angeles Department of Oncology University College London Cancer Institute Department of Mathematics Boise State University Departments of Genetics and Computer Science Yale University

Directed graphs are a natural model for many phenomena, in particular scientific knowledge graphs such as molecular interaction or chemical reaction networks that define cellular signaling relationships. In these situations, source nodes typically have distinct biophysical properties from sinks. Due to their ordered and unidirectional relationships, many such networks also have hierarchical and multiscale structure. However, the majority of methods performing node- and edge-level tasks in machine learning do not take these properties into account, and thus have not been leveraged effectively for scientific tasks such as cellular signaling network inference. We propose a new framework called Directed Scattering Autoencoder (DSAE) which uses a directed version of a geometric scattering transform, combined with the non-linear dimensionality reduction properties of an autoencoder and the geometric properties of the hyperbolic space to learn latent hierarchies. We show this method outperforms numerous others on tasks such as embedding directed graphs and learning cellular signaling networks.

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Multiscale reorganization of the genome following DNA damage facilitates chromosome translocations via nuclear actin polymerization(vol 30, pg 99, 2023)

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NATURE STRUCTURAL & MOLECULAR biology 2023年第7期30卷 1048-1048页

作者： Zagelbaum, Jennifer Schooley, Allana Zhao, Junfei Schrank, Benjamin R. Callen, Elsa Zha, Shan Gottesman, Max E. Nussenzweig, Andre Rabadan, Raul Dekker, Job Gautier, Jean Institute for Cancer Genetics Columbia University Vagelos College of Physicians and Surgeons New York NY USA Integrated Program in Cellular Molecular and Biomedical Studies Columbia University Vagelos College of Physicians and Surgeons New York NY USA Department of Systems Biology University of Massachusetts Medical School Worcester MA USA Department of Systems Biology Columbia University Vagelos College of Physicians and Surgeons New York NY USA Laboratory of Genome Integrity National Institutes of Health Bethesda MD USA Department of Pathology and Cell Biology and Department of Pediatrics Columbia University Vagelos College of Physicians and Surgeons New York NY USA Herbert Irving Comprehensive Cancer Center Columbia University Vagelos College of Physicians and Surgeons New York NY USA Department of Biochemistry and Biophysics Columbia University Vagelos College of Physicians and Surgeons New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA Department of Genetics and Development Columbia University Vagelos College of Physicians and Surgeons New York NY USA

Nuclear actin-based movements have been shown to orchestrate clustering of DNA double-strand breaks (DSBs) into homology-directed repair domains. Here we describe multiscale three-dimensional genome reorganization following DNA damage and analyze the contribution of the nuclear WASP-ARP2/3-actin pathway toward chromatin topology alterations and pathologic repair. Hi-C analysis reveals genome-wide, DNA damage-induced chromatin compartment flips facilitated by ARP2/3 that enrich for open, A compartments. Damage promotes interactions between DSBs, which in turn facilitate aberrant, actin-dependent intra- and inter-chromosomal rearrangements. Our work establishes that clustering of resected DSBs into repair domains by nuclear actin assembly is coordinated with multiscale alterations in genome architecture that enable homology-directed repair while also increasing nonhomologous end-joining-dependent translocation frequency.

关键词： Chromatin structure DNA damage and repair Nuclear organization

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SPATIAL ATTENTION KINETIC NETWORK WITH E(N)-EQUIVARIANCE

arXiv

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arXiv 2023年

作者： Wang, Yuanqing Chodera, John D. Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States 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, CC BY.

关键词： Dynamical systems

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Methods for multiplexing single-cell multi-omics

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Nature methods 2025年 2025 May 26页

作者： Laura C Kida Caleb A Lareau Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. lareauc@***.

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Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer

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Cell and Bioscience 2023年第1期13卷 1页

作者： Fan, Yu-Ching Fong, Yu-Cin Kuo, Chun-Tse Li, Chia-Wei Chen, Wei-Yu Lin, Jian-Da Bürtin, Florian Linnebacher, Michael Bui, Quoc Thang Lee, Kuan-Der Tsai, Yuan-Chin Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Department of Pathology Wan Fang Hospital Taipei Medical University Taipei Taiwan Department of Pathology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Biochemical Science and Technology College of Life Science National Taiwan University Taipei City 10617 Taiwan Center for Computational and Systems Biology National Taiwan University Taipei City 10617 Taiwan Clinic of General Surgery University Medical Center Rostock Schillingallee 35 Rostock 18057 Germany Clinic of General Surgery Molecular Oncology and Immunotherapy University Medical Center Rostock Schillingallee 69 Rostock 18057 Germany International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM) School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Post-Baccalaureate Medicine College of Medicine Natioanl Chung Hsing University Taichung Taiwan Cell Therapy and Regenerative Medicine Center and Comprehensive Cancer Center Taichung Veterans General Hospital Taichung Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan

Background: Pancreatic ductal adenocarcinoma (PDA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory cytokine;however, its contribution to cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1Ra in malignant progression of PDA. Results: Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1Ra expression is elevated in human PDA and positively associated with malignant progression of PDA. To study the biological function of IL-1Ra in tumors, we generated a set of mouse pancreatic cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1Ra, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in CD8⁺ T cells and a decrease in CD11b⁺Ly6G⁻ immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1Ra on immune cells, we utilized a luciferase-based reporter CD4⁺ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in CD8⁺ T cells, and mice immunized with ovalbumin. We showed that IL-1Ra suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes. Conclusions: Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1Ra, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of

关键词： IFN-γ Immunosuppression interleukin-1 receptor antagonist Pancreatic adenocarcinoma Patient-derived xenograft Tumor microenvironment

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Fundamental immuneoncogenicity trade-offs define driver mutation fitness (vol 606, pg 172, 2022)

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NATURE 2022年第7914期606卷 E5-E5页

作者： Hoyos, David Zappasodi, Roberta Schulze, Isabell Sethna, Zachary de Andrade, Kelvin Cesar Bajorin, Dean F. Bandlamudi, Chaitanya Callahan, Margaret K. Funt, Samuel A. Hadrup, Sine R. Holm, Jeppe S. Rosenberg, Jonathan E. Shah, Sohrab P. Vazquez-Garcia, Ignacio Weigelt, Britta Wu, Michelle Zamarin, Dmitriy Campitelli, Laura F. Osborne, Edward J. Klinger, Mark Robins, Harlan S. Khincha, Payal P. Savage, Sharon A. Balachandran, Vinod P. Wolchok, Jedd D. Hellmann, Matthew D. Merghoub, Taha Levine, Arnold J. Luksza, Marta Greenbaum, Benjamin D. Computational Oncology Department of Epidemiology & Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Swim Across America Laboratory and Ludwig Collaborative Immunology Program Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Department of Medicine Weill Cornell Medical College New York NY USA Parker Institute for Cancer Immunotherapy Memorial Sloan Kettering Cancer Center New York NY USA Immunology and Microbial Pathogenesis Program Weill Cornell Graduate School of Medical Sciences New York NY USA Hepatopancreatobiliary Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA Division of Cancer Epidemiology and Genetics Clinical Genetics Branch National Cancer Institute National Institutes of Health Rockville MD USA Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA Kravis Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY USA Experimental and Translational Immunology Health Technology Technical University of Denmark Lyngby Denmark Physiology Biophysics & Systems Biology Weill Cornell Medicine Weill Cornell Medical College New York NY USA Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA Adaptive Biotechnologies Seattle WA USA David M. Rubenstein Center for Pancreatic Cancer Research Memorial Sloan Kettering Cancer Center New York NY USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA Thoracic Oncology Service Memorial Sloan Kettering Cancer Center New York NY USA Simons Center for Systems Biology Institute for Advanced Study Princeton NJ USA Department of Oncological Sciences Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3,4,5,6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.

关键词： computational models Evolutionary theory Tumour immunology Tumour-suppressor proteins

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