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

Nature Communications
Qing JiQi Li

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.

Associated Datasets

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Citations

Sep 24, 2020·Cancers·Alexander Jorge CortezKatarzyna Marta Lisowska
Sep 23, 2020·International Journal of Molecular Sciences·Issraa ShoucairCathie Garnis
Oct 13, 2020·Frontiers in Pharmacology·Chao-Yue SuJian-Ye Zhang
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Methods Mentioned

BETA
PCR
electron microscopy
enzyme-linked immunosorbent assay
immunoprecipitation
ChIP
co-immunoprecipitation
Co-IP
bioluminescence
xenograft
transfection

Software Mentioned

novoalign
Graphpad prism
Nanosight
DAVID
SPSS
MaxQuant
Perseus

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