ZIP1 + fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn 2+ transfer

Tumour-stroma cell interactions impact cancer progression and therapy responses. Intercellular communication between fibroblasts and cancer cells using various soluble mediators has often been reported. In this study, we find that a zinc-transporter (ZIP1) positive tumour-associated fibroblast subse...

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Published inNature communications Vol. 13; no. 1; p. 5919
Main Authors Ni, Chen, Lou, Xiaohan, Yao, Xiaohan, Wang, Linlin, Wan, Jiajia, Duan, Xixi, Liang, Jialu, Zhang, Kaili, Yang, Yuanyuan, Zhang, Li, Sun, Chanjun, Li, Zhenzhen, Wang, Ming, Zhu, Linyu, Lv, Dekang, Qin, Zhihai
Format Journal Article
LanguageEnglish
Published England 07.10.2022
Subjects
Animals
Cell Communication - physiology
Doxorubicin - metabolism
Doxorubicin - pharmacology
Fibroblasts - metabolism
Gap Junctions - metabolism
Humans
Lung Neoplasms - pathology
Mice
Zinc - metabolism
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Summary:Tumour-stroma cell interactions impact cancer progression and therapy responses. Intercellular communication between fibroblasts and cancer cells using various soluble mediators has often been reported. In this study, we find that a zinc-transporter (ZIP1) positive tumour-associated fibroblast subset is enriched after chemotherapy and directly interconnects lung cancer cells with gap junctions. Using single-cell RNA sequencing, we identify several fibroblast subpopulations, among which Zip1 fibroblasts are highly enriched in mouse lung tumours after doxorubicin treatment. ZIP1 expression on fibroblasts enhances gap junction formation in cancer cells by upregulating connexin-43. Acting as a Zn reservoir, ZIP1 fibroblasts absorb and transfer Zn to cancer cells, leading to ABCB1-mediated chemoresistance. Clinically, ZIP1 stromal fibroblasts are also associated with chemoresistance in human lung cancers. Taken together, our results reveal a mechanism by which fibroblasts interact directly with tumour cells via gap junctions and contribute to chemoresistance in lung cancer.
ISSN:2041-1723