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

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, Yihai Cao, Guoxiang Cai (), Yan Wang () and Qi Li ()
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Qing Ji: Shanghai University of Traditional Chinese Medicine
Lihong Zhou: Shanghai University of Traditional Chinese Medicine
Hua Sui: Shanghai University of Traditional Chinese Medicine
Liu Yang: Shanghai University of Traditional Chinese Medicine
Xinnan Wu: Shanghai University of Traditional Chinese Medicine
Qing Song: Shanghai University of Traditional Chinese Medicine
Ru Jia: Shanghai University of Traditional Chinese Medicine
Ruixiao Li: 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
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
Guoxiang Cai: Fudan University Shanghai Cancer Center
Yan Wang: Shanghai University of Traditional Chinese Medicine
Qi Li: Shanghai University of Traditional Chinese Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14869-x

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