IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57429-x.html
   My bibliography  Save this article

Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control

Author

Listed:
  • Dimitri Belenki

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Paulina Richter-Pechanska

    (Campus Virchow Klinikum)

  • Zhiting Shao

    (Campus Virchow Klinikum)

  • Animesh Bhattacharya

    (Campus Virchow Klinikum)

  • Andrea Lau

    (Campus Virchow Klinikum)

  • José Américo Nabuco Leva Ferreira de Freitas

    (Faculté de Médecine de Créteil)

  • Gregor Kandler

    (Campus Virchow Klinikum)

  • Timon P. Hick

    (Campus Virchow Klinikum
    Humboldt-Universität zu Berlin)

  • Xiurong Cai

    (Campus Virchow Klinikum)

  • Eva Scharnagl

    (Medical Faculty)

  • Aitomi Bittner

    (Campus Virchow Klinikum)

  • Martin Schönlein

    (Campus Virchow Klinikum
    University Medical Center Hamburg-Eppendorf
    Vienna BioCenter (VBC))

  • Julia Kase

    (Campus Virchow Klinikum)

  • Katharina Pardon

    (Campus Virchow Klinikum)

  • Bernadette Brzezicha

    (Experimental Pharmacology & Oncology Berlin-Buch GmbH)

  • Nina Thiessen

    (Berlin Institute of Health)

  • Oliver Bischof

    (Faculté de Médecine de Créteil)

  • Jan R. Dörr

    (Campus Virchow Klinikum
    Charité-Universitätsmedizin Berlin
    Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin)

  • Maurice Reimann

    (Campus Virchow Klinikum)

  • Maja Milanovic

    (Campus Virchow Klinikum
    Campus Benjamin Franklin
    partner site Berlin)

  • Jing Du

    (Medical Research Center and Department of Oncology Binzhou Medical University Hospital)

  • Yong Yu

    (Medical Faculty)

  • Björn Chapuy

    (Campus Benjamin Franklin)

  • Soyoung Lee

    (Campus Virchow Klinikum
    Medical Faculty)

  • Ulf Leser

    (Humboldt-Universität zu Berlin)

  • Claus Scheidereit

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Jana Wolf

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Free University Berlin)

  • Dorothy N. Y. Fan

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    partner site Berlin)

  • Clemens A. Schmitt

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Medical Faculty
    partner site Berlin)

Abstract

Cellular senescence is a stress-inducible state switch relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, senescent cells are characterized by profound chromatin remodeling and transcriptional reprogramming. We show here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary human and murine B-cell lymphoma. We find myeloid transcription factor (TF) networks, specifically AP-1-, C/EBPβ- and PU.1-governed transcriptional programs, enriched in TIS but not in equally chemotherapy-exposed senescence-incapable cancer cells. Dependent on these master TF, TIS lymphoma cells adopt a lineage-promiscuous state with properties of monocytic-dendritic cell (DC) differentiation. TIS lymphoma cells are preferentially lysed by T-cells in vitro, and mice harboring DC-skewed Eμ-myc lymphoma experience significantly longer tumor-free survival. Consistently, superior long-term outcome is also achieved in diffuse large B-cell lymphoma patients with high expression of a TIS-related DC signature. In essence, these data demonstrate a therapeutically exploitable, prognostically favorable immunogenic role of senescence-dependent aberrant myeloid plasticity in B-cell lymphoma.

Suggested Citation

  • Dimitri Belenki & Paulina Richter-Pechanska & Zhiting Shao & Animesh Bhattacharya & Andrea Lau & José Américo Nabuco Leva Ferreira de Freitas & Gregor Kandler & Timon P. Hick & Xiurong Cai & Eva Schar, 2025. "Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57429-x
    DOI: 10.1038/s41467-025-57429-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57429-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57429-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Soyoung Lee & Yong Yu & Jakob Trimpert & Fahad Benthani & Mario Mairhofer & Paulina Richter-Pechanska & Emanuel Wyler & Dimitri Belenki & Sabine Kaltenbrunner & Maria Pammer & Lea Kausche & Theresa C., 2021. "Virus-induced senescence is a driver and therapeutic target in COVID-19," Nature, Nature, vol. 599(7884), pages 283-289, November.
    2. Jean-Philippe Coppé & Christopher K Patil & Francis Rodier & Yu Sun & Denise P Muñoz & Joshua Goldstein & Peter S Nelson & Pierre-Yves Desprez & Judith Campisi, 2008. "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor," PLOS Biology, Public Library of Science, vol. 6(12), pages 1-1, December.
    3. Cristina Aguilera & Kentaro Nakagawa & Rocio Sancho & Atanu Chakraborty & Brian Hendrich & Axel Behrens, 2011. "c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex," Nature, Nature, vol. 469(7329), pages 231-235, January.
    4. Vasanthi S. Viswanathan & Matthew J. Ryan & Harshil D. Dhruv & Shubhroz Gill & Ossia M. Eichhoff & Brinton Seashore-Ludlow & Samuel D. Kaffenberger & John K. Eaton & Kenichi Shimada & Andrew J. Aguirr, 2017. "Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway," Nature, Nature, vol. 547(7664), pages 453-457, July.
    5. Jan R. Dörr & Yong Yu & Maja Milanovic & Gregor Beuster & Christin Zasada & J. Henry M. Däbritz & Jan Lisec & Dido Lenze & Anne Gerhardt & Katharina Schleicher & Susanne Kratzat & Bettina Purfürst & S, 2013. "Synthetic lethal metabolic targeting of cellular senescence in cancer therapy," Nature, Nature, vol. 501(7467), pages 421-425, September.
    6. Kolja Schleich & Julia Kase & Jan R. Dörr & Saskia Trescher & Animesh Bhattacharya & Yong Yu & Elizabeth M. Wailes & Dorothy N. Y. Fan & Philipp Lohneis & Maja Milanovic & Andrea Lau & Dido Lenze & Mi, 2020. "H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    7. Melanie Braig & Soyoung Lee & Christoph Loddenkemper & Cornelia Rudolph & Antoine H.F.M. Peters & Brigitte Schlegelberger & Harald Stein & Bernd Dörken & Thomas Jenuwein & Clemens A. Schmitt, 2005. "Oncogene-induced senescence as an initial barrier in lymphoma development," Nature, Nature, vol. 436(7051), pages 660-665, August.
    8. Maja Milanovic & Dorothy N. Y. Fan & Dimitri Belenki & J. Henry M. Däbritz & Zhen Zhao & Yong Yu & Jan R. Dörr & Lora Dimitrova & Dido Lenze & Ines A. Monteiro Barbosa & Marco A. Mendoza-Parra & Tamar, 2018. "Senescence-associated reprogramming promotes cancer stemness," Nature, Nature, vol. 553(7686), pages 96-100, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Huiru Bai & Xiaoqin Liu & Meizhen Lin & Yuan Meng & Ruolan Tang & Yajing Guo & Nan Li & Michael F. Clarke & Shang Cai, 2024. "Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Cox, Lynne S., 2022. "Therapeutic approaches to treat and prevent age-related diseases through understanding the underlying biological drivers of ageing," The Journal of the Economics of Ageing, Elsevier, vol. 23(C).
    3. Joae Joung & Yekang Heo & Yeonju Kim & Jaejin Kim & Haebeen Choi & Taerang Jeon & Yeji Jang & Eun-Jung Kim & Sang Heon Lee & Jae Myoung Suh & Stephen J. Elledge & Mi-Sung Kim & Chanhee Kang, 2025. "Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    4. Bin Huang & Hui Wang & Shuo Liu & Meng Hao & Dan Luo & Yi Zhou & Ying Huang & Yong Nian & Lei Zhang & Bo Chu & Chengqian Yin, 2025. "Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Christopher A. Waudby & Saul Alvarez-Teijeiro & E. Josue Ruiz & Simon Suppinger & Nikos Pinotsis & Paul R. Brown & Axel Behrens & John Christodoulou & Anastasia Mylona, 2022. "An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Karl N. Miller & Brightany Li & Hannah R. Pierce-Hoffman & Shreeya Patel & Xue Lei & Adarsh Rajesh & Marcos G. Teneche & Aaron P. Havas & Armin Gandhi & Carolina Cano Macip & Jun Lyu & Stella G. Victo, 2025. "p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    7. Cathy Pichol-Thievend & Oceane Anezo & Aafrin M. Pettiwala & Guillaume Bourmeau & Remi Montagne & Anne-Marie Lyne & Pierre-Olivier Guichet & Pauline Deshors & Alberto Ballestín & Benjamin Blanchard & , 2024. "VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    8. Fathima Athar & Zhizhong Zheng & Sebastien Riquier & Max Zacher & J. Yuyang Lu & Yang Zhao & Valentin Volobaev & Dominic Alcock & Alex Galazyuk & Lisa Noelle Cooper & Tony Schountz & Lin-Fa Wang & Emm, 2025. "Limited cell-autonomous anticancer mechanisms in long-lived bats," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    9. Chen Wang & Hideki Tanizawa & Connor Hill & Aaron Havas & Qiang Zhang & Liping Liao & Xue Hao & Xue Lei & Lu Wang & Hao Nie & Yuan Qi & Bin Tian & Alessandro Gardini & Andrew V. Kossenkov & Aaron Gold, 2024. "METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Jun Jiang & Lili Yang & Qianqian Xie & Xi Liu & Jie Jiang & Jie Zhang & Shuping Zhang & Huizhen Zheng & Wenjie Li & Xiaoming Cai & Sijin Liu & Ruibin Li, 2024. "Synthetic vectors for activating the driving axis of ferroptosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. Ines Sturmlechner & Chance C. Sine & Karthik B. Jeganathan & Cheng Zhang & Raul O. Fierro Velasco & Darren J. Baker & Hu Li & Jan M. Deursen, 2022. "Senescent cells limit p53 activity via multiple mechanisms to remain viable," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    12. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Jenna E. Leeuwen & Wail Ba-Alawi & Emily Branchard & Jennifer Cruickshank & Wiebke Schormann & Joseph Longo & Jennifer Silvester & Peter L. Gross & David W. Andrews & David W. Cescon & Benjamin Haibe-, 2022. "Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    14. Laura Solé & Teresa Lobo-Jarne & Daniel Álvarez-Villanueva & Josune Alonso-Marañón & Yolanda Guillén & Marta Guix & Irene Sangrador & Catalina Rozalén & Anna Vert & Antonio Barbachano & Joan Lop & Mar, 2022. "p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Heike Chauvistré & Batool Shannan & Sheena M. Daignault-Mill & Robert J. Ju & Daniel Picard & Stefanie Egetemaier & Renáta Váraljai & Christine S. Gibhardt & Antonio Sechi & Farnusch Kaschani & Oliver, 2022. "Persister state-directed transitioning and vulnerability in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Mark A. Sanborn & Xinge Wang & Shang Gao & Yang Dai & Jalees Rehman, 2025. "Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    17. Yukinari Haraoka & Yuki Akieda & Yuri Nagai & Chihiro Mogi & Tohru Ishitani, 2022. "Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    19. Laura Heydemann & Małgorzata Ciurkiewicz & Georg Beythien & Kathrin Becker & Klaus Schughart & Stephanie Stanelle-Bertram & Berfin Schaumburg & Nancy Mounogou-Kouassi & Sebastian Beck & Martin Zickler, 2023. "Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    20. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57429-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.