IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-47949-3.html
   My bibliography  Save this article

Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer

Author

Listed:
  • Meirion Raymant

    (University of Liverpool)

  • Yuliana Astuti

    (University of Liverpool)

  • Laura Alvaro-Espinosa

    (Spanish National Cancer Research Centre (CNIO))

  • Daniel Green

    (University of Liverpool)

  • Valeria Quaranta

    (University of Liverpool)

  • Gaia Bellomo

    (University of Liverpool)

  • Mark Glenn

    (University of Liverpool)

  • Vatshala Chandran-Gorner

    (University of Liverpool)

  • Daniel H. Palmer

    (University of Liverpool)

  • Christopher Halloran

    (University of Liverpool)

  • Paula Ghaneh

    (University of Liverpool)

  • Neil C. Henderson

    (University of Edinburgh
    University of Edinburgh)

  • Jennifer P. Morton

    (University of Glasgow)

  • Manuel Valiente

    (Spanish National Cancer Research Centre (CNIO))

  • Ainhoa Mielgo

    (University of Liverpool)

  • Michael C. Schmid

    (University of Liverpool)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage–fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

Suggested Citation

  • Meirion Raymant & Yuliana Astuti & Laura Alvaro-Espinosa & Daniel Green & Valeria Quaranta & Gaia Bellomo & Mark Glenn & Vatshala Chandran-Gorner & Daniel H. Palmer & Christopher Halloran & Paula Ghan, 2024. "Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47949-3
    DOI: 10.1038/s41467-024-47949-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-47949-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-47949-3?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. Joan Massagué & Anna C. Obenauf, 2016. "Metastatic colonization by circulating tumour cells," Nature, Nature, vol. 529(7586), pages 298-306, January.
    2. Akshay T. Krishnamurty & Justin A. Shyer & Minh Thai & Vineela Gandham & Matthew B. Buechler & Yeqing Angela Yang & Rachana N. Pradhan & Amber W. Wang & Patricia L. Sanchez & Yan Qu & Beatrice Breart , 2022. "LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity," Nature, Nature, vol. 611(7934), pages 148-154, November.
    3. Aveline Filliol & Yoshinobu Saito & Ajay Nair & Dianne H. Dapito & Le-Xing Yu & Aashreya Ravichandra & Sonakshi Bhattacharjee & Silvia Affo & Naoto Fujiwara & Hua Su & Qiuyan Sun & Thomas M. Savage & , 2022. "Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis," Nature, Nature, vol. 610(7931), pages 356-365, October.
    4. Michael Bartoschek & Nikolay Oskolkov & Matteo Bocci & John Lövrot & Christer Larsson & Mikael Sommarin & Chris D. Madsen & David Lindgren & Gyula Pekar & Göran Karlsson & Markus Ringnér & Jonas Bergh, 2018. "Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    5. P. Ramachandran & R. Dobie & J. R. Wilson-Kanamori & E. F. Dora & B. E. P. Henderson & N. T. Luu & J. R. Portman & K. P. Matchett & M. Brice & J. A. Marwick & R. S. Taylor & M. Efremova & R. Vento-Tor, 2019. "Resolving the fibrotic niche of human liver cirrhosis at single-cell level," Nature, Nature, vol. 575(7783), pages 512-518, November.
    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. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    2. Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    4. LiangYu Zhao & Sha Han & HengChuan Su & JianYing Li & ErLei Zhi & Peng Li & ChenCheng Yao & RuHui Tian & HuiXing Chen & HuiRong Chen & JiaQiang Luo & ChenKun Shi & ZhiYong Ji & JianLin Hu & Gang Wu & , 2022. "Single-cell transcriptome atlas of the human corpus cavernosum," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Agnieska Brazovskaja & Tomás Gomes & Rene Holtackers & Philipp Wahle & Christiane Körner & Zhisong He & Theresa Schaffer & Julian Connor Eckel & René Hänsel & Malgorzata Santel & Makiko Seimiya & Timm, 2024. "Cell atlas of the regenerating human liver after portal vein embolization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Yingying Zhao & Hongmei Yu & Jiajun Li & Jiali Qian & Miao Li & Xi Zhang & Mimi Wang & Yaohui Wang & Yinying Dong & Yang You & Qiwen Zhou & Dongmei Gao & Yan Zhao & Binbin Liu & Rongxin Chen & Zhengga, 2025. "A glucose-enriched lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs in hepatocellular carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-26, December.
    7. Vincent Geldhof & Laura P. M. H. Rooij & Liliana Sokol & Jacob Amersfoort & Maxim Schepper & Katerina Rohlenova & Griet Hoste & Adriaan Vanderstichele & Anne-Marie Delsupehe & Edoardo Isnaldi & Naima , 2022. "Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. T. Hautz & S. Salcher & M. Fodor & G. Sturm & S. Ebner & A. Mair & M. Trebo & G. Untergasser & S. Sopper & B. Cardini & A. Martowicz & J. Hofmann & S. Daum & M. Kalb & T. Resch & F. Krendl & A. Weisse, 2023. "Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Lisa Veghini & Davide Pasini & Rui Fang & Pietro Delfino & Dea Filippini & Christian Neander & Caterina Vicentini & Elena Fiorini & Francesca Lupo & Sabrina L. D’Agosto & Carmine Carbone & Antonio Ago, 2024. "Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    10. Julia M. Houthuijzen & Roebi Bruijn & Eline Burg & Anne Paulien Drenth & Ellen Wientjens & Tamara Filipovic & Esme Bullock & Chiara S. Brambillasca & Emilia M. Pulver & Marja Nieuwland & Iris Rink & F, 2023. "CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    11. Huachun Cui & Sami Banerjee & Na Xie & Musaddique Hussain & Ashish Jaiswal & Hongli Liu & Tejaswini Kulkarni & Veena B. Antony & Rui-Ming Liu & Marco Colonna & Gang Liu, 2025. "TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    12. Yi Duan & Huikuan Chu & Katharina Brandl & Lu Jiang & Suling Zeng & Nairika Meshgin & Eleni Papachristoforou & Josepmaria Argemi & Beatriz G. Mendes & Yanhan Wang & Hua Su & Weizhong Sun & Cristina Ll, 2021. "CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    13. Rong Xiao & Deshu Xu & Meili Zhang & Zhanghua Chen & Li Cheng & Songjie Du & Mingfei Lu & Tonghai Zhou & Ruoyan Li & Fan Bai & Yue Huang, 2024. "Aneuploid embryonic stem cells drive teratoma metastasis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Adriana A. de Jesus & Guibin Chen & Dan Yang & Tomas Brdicka & Natasha M. Ruth & David Bennin & Dita Cebecauerova & Hana Malcova & Helen Freeman & Neil Martin & Karel Svojgr & Murray H. Passo & Farzan, 2023. "Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    15. Zhiyuan Zheng & Ya-nan Li & Shanfen Jia & Mengting Zhu & Lijuan Cao & Min Tao & Jingting Jiang & Shenghua Zhan & Yongjing Chen & Ping-Jin Gao & Weiguo Hu & Ying Wang & Changshun Shao & Yufang Shi, 2021. "Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    16. Saba Nayar & Jason D. Turner & Saba Asam & Eanna Fennell & Matthew Pugh & Serena Colafrancesco & Onorina Berardicurti & Charlotte G. Smith & Joe Flint & Ana Teodosio & Valentina Iannizzotto & David H., 2025. "Molecular and spatial analysis of tertiary lymphoid structures in Sjogren’s syndrome," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    17. Sabrina Schütz & Llorenç Solé-Boldo & Carlota Lucena-Porcel & Jochen Hoffmann & Alexander Brobeil & Anke S. Lonsdorf & Manuel Rodríguez-Paredes & Frank Lyko, 2023. "Functionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Yuxiang Song & Na Li & Shang Jiang & Kexin Wang & Guoyue Lv & Zhongqi Fan & Xiliang Du & Wenwen Gao & Lin Lei & Zhe Wang & Guowen Liu & Xinwei Li, 2025. "Microbiota-derived H2S induces c-kit+ cDC1 autophagic cell death and liver inflammation in metabolic dysfunction-associated steatohepatitis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    19. Huapan Fang & Zhaopei Guo & Jie Chen & Lin Lin & Yingying Hu & Yanhui Li & Huayu Tian & Xuesi Chen, 2021. "Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    20. Kaiyuan Wang & Xuanbo Zhang & Hao Ye & Xia Wang & Zhijin Fan & Qi Lu & Songhao Li & Jian Zhao & Shunzhe Zheng & Zhonggui He & Qianqian Ni & Xiaoyuan Chen & Jin Sun, 2023. "Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, 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:15:y:2024:i:1:d:10.1038_s41467-024-47949-3. 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.