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Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation

Author

Listed:
  • Qing Ji

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Lihong Zhou

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Hua Sui

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Liu Yang

    (Shanghai University of Traditional Chinese Medicine)

  • Xinnan Wu

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Qing Song

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Ru Jia

    (Shanghai University of Traditional Chinese Medicine)

  • Ruixiao Li

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Jian Sun

    (Shanghai University of Traditional Chinese Medicine)

  • Ziyuan Wang

    (Shanghai University of Traditional Chinese Medicine)

  • Ningning Liu

    (Shanghai University of Traditional Chinese Medicine)

  • Yuanyuan Feng

    (Shanghai University of Traditional Chinese Medicine)

  • Xiaoting Sun

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Gang Cai

    (Shanghai University of Traditional Chinese Medicine)

  • Yu Feng

    (Shanghai University of Traditional Chinese Medicine)

  • Jianfeng Cai

    (University of South Florida)

  • Yihai Cao

    (Shanghai University of Traditional Chinese Medicine
    Karolinska Institutet)

  • Guoxiang Cai

    (Fudan University Shanghai Cancer Center)

  • Yan Wang

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

  • Qi Li

    (Shanghai University of Traditional Chinese Medicine
    Shanghai University of Traditional Chinese Medicine)

Abstract

Tumor metastasis is a hallmark of cancer. Metastatic cancer cells often reside in distal tissues and organs in their dormant state. Mechanisms underlying the pre-metastatic niche formation are poorly understood. Here we show that in a colorectal cancer (CRC) model, primary tumors release integrin beta-like 1 (ITGBL1)-rich extracellular vesicles (EVs) to the circulation to activate resident fibroblasts in remote organs. The activated fibroblasts induce the pre-metastatic niche formation and promote metastatic cancer growth by secreting pro-inflammatory cytokine, such as IL-6 and IL-8. Mechanistically, the primary CRC-derived ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-κB signaling pathway to activate fibroblasts. Consequently, the activated fibroblasts produce high levels of pro-inflammatory cytokines to promote metastatic cancer growth. These findings uncover a tumor–stromal interaction in the metastatic tumor microenvironment and an intimate signaling communication between primary tumors and metastases through the ITGBL1-loaded EVs. Targeting the EVs-ITGBL1-CAFs-TNFAIP3-NF-κB signaling axis provides an attractive approach for treating metastatic diseases.

Suggested Citation

  • Qing Ji & Lihong Zhou & Hua Sui & Liu Yang & Xinnan Wu & Qing Song & Ru Jia & Ruixiao Li & Jian Sun & Ziyuan Wang & Ningning Liu & Yuanyuan Feng & Xiaoting Sun & Gang Cai & Yu Feng & Jianfeng Cai & Yi, 2020. "Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14869-x
    DOI: 10.1038/s41467-020-14869-x
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    Cited by:

    1. Victoria Stary & Ram V. Pandey & Julia List & Lisa Kleissl & Florian Deckert & Julijan Kabiljo & Johannes Laengle & Vasileios Gerakopoulos & Rudolf Oehler & Lukas Watzke & Matthias Farlik & Samuel W. , 2024. "Dysfunctional tumor-infiltrating Vδ1 + T lymphocytes in microsatellite-stable colorectal cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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