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

Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance. 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, ZIP1(high) 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.