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VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Author

Listed:
  • Rosandra N. Kaplan

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology
    Department of Pediatrics)

  • Rebecca D. Riba

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • Stergios Zacharoulis

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology
    Department of Pediatrics)

  • Anna H. Bramley

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • Loïc Vincent

    (Genetic Medicine)

  • Carla Costa

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • Daniel D. MacDonald

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • David K. Jin

    (Genetic Medicine)

  • Koji Shido

    (Genetic Medicine)

  • Scott A. Kerns

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • Zhenping Zhu

    (Imclone Systems Incorporated)

  • Daniel Hicklin

    (Imclone Systems Incorporated)

  • Yan Wu

    (Imclone Systems Incorporated)

  • Jeffrey L. Port

    (Surgery, Weill Cornell Medical College of Cornell University)

  • Nasser Altorki

    (Surgery, Weill Cornell Medical College of Cornell University)

  • Elisa R. Port

    (Surgery, Memorial Sloan-Kettering Cancer Center)

  • Davide Ruggero

    (Fox Chase Cancer Center)

  • Sergey V. Shmelkov

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology
    Genetic Medicine)

  • Kristian K. Jensen

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology)

  • Shahin Rafii

    (Howard Hughes Medical Institute
    Genetic Medicine)

  • David Lyden

    (Department of Pediatrics and the Children's Blood Foundation Laboratories
    Cell and Developmental Biology
    Department of Pediatrics)

Abstract

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1+ cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin α4β1), and that tumour-specific growth factors upregulate fibronectin—a VLA-4 ligand—in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Suggested Citation

  • Rosandra N. Kaplan & Rebecca D. Riba & Stergios Zacharoulis & Anna H. Bramley & Loïc Vincent & Carla Costa & Daniel D. MacDonald & David K. Jin & Koji Shido & Scott A. Kerns & Zhenping Zhu & Daniel Hi, 2005. "VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche," Nature, Nature, vol. 438(7069), pages 820-827, December.
  • Handle: RePEc:nat:nature:v:438:y:2005:i:7069:d:10.1038_nature04186
    DOI: 10.1038/nature04186
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    Cited by:

    1. 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.
    2. Keyang Xu & Ai Fu & Zhaoyi Li & Liangbin Miao & Zhonghan Lou & Keying Jiang & Condon Lau & Tao Su & Tiejun Tong & Jianfeng Bao & Aiping Lyu & Hiu Yee Kwan, 2024. "Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yibing Han & Takeshi Tomita & Masayoshi Kato & Norihiro Ashihara & Yumiko Higuchi & Hisanori Matoba & Weiyi Wang & Hikaru Hayashi & Yuji Itoh & Satoshi Takahashi & Hiroshi Kurita & Jun Nakayama & Nobu, 2023. "Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Lufei Sui & Suming Wang & Debolina Ganguly & Tyler P. El Rayes & Cecilie Askeland & Astrid Børretzen & Danielle Sim & Ole Johan Halvorsen & Gøril Knutsvik & Jarle Arnes & Sura Aziz & Svein Haukaas & W, 2022. "PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Nieves Montenegro-Navarro & Claudia García-Báez & Melissa García-Caballero, 2023. "Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Flavia A. Graca & Mamta Rai & Liam C. Hunt & Anna Stephan & Yong-Dong Wang & Brittney Gordon & Ruishan Wang & Giovanni Quarato & Beisi Xu & Yiping Fan & Myriam Labelle & Fabio Demontis, 2022. "The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    7. Yi Zhou & Peng Ke & Xiaoyan Bao & Honghui Wu & Yiyi Xia & Zhentao Zhang & Haiqing Zhong & Qi Dai & Linjie Wu & Tiantian Wang & Mengting Lin & Yaosheng Li & Xinchi Jiang & Qiyao Yang & Yiying Lu & Xinc, 2022. "Peptide nano-blanket impedes fibroblasts activation and subsequent formation of pre-metastatic niche," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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