ZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer

Chen Ni (), Xiaohan Lou, Xiaohan Yao, Linlin Wang, Jiajia Wan, Xixi Duan, Jialu Liang, Kaili Zhang, Yuanyuan Yang, Li Zhang, Chanjun Sun, Zhenzhen Li, Ming Wang, Linyu Zhu, Dekang Lv () and Zhihai Qin ()
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Chen Ni: the First Affiliated Hospital of Zhengzhou University
Xiaohan Lou: the First Affiliated Hospital of Zhengzhou University
Xiaohan Yao: the First Affiliated Hospital of Zhengzhou University
Linlin Wang: the First Affiliated Hospital of Zhengzhou University
Jiajia Wan: the First Affiliated Hospital of Zhengzhou University
Xixi Duan: the First Affiliated Hospital of Zhengzhou University
Jialu Liang: the First Affiliated Hospital of Zhengzhou University
Kaili Zhang: the First Affiliated Hospital of Zhengzhou University
Yuanyuan Yang: the First Affiliated Hospital of Zhengzhou University
Li Zhang: the First Affiliated Hospital of Zhengzhou University
Chanjun Sun: the First Affiliated Hospital of Zhengzhou University
Zhenzhen Li: the First Affiliated Hospital of Zhengzhou University
Ming Wang: the First Affiliated Hospital of Zhengzhou University
Linyu Zhu: the First Affiliated Hospital of Zhengzhou University
Dekang Lv: Dalian Medical University
Zhihai Qin: the First Affiliated Hospital of Zhengzhou University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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 Zn2+ reservoir, ZIP1+ fibroblasts absorb and transfer Zn2+ to cancer cells, leading to ABCB1-mediated chemoresistance. Clinically, ZIP1high 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.

Date: 2022
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DOI: 10.1038/s41467-022-33521-4

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