Fig. 9: ZIP1⁺ fibroblasts interconnect lung cancer cells via upregulating CX43 and promote chemoresistance by Zn²⁺ transfer.

Chemotherapy treatment induces Zn²⁺ released from dying cancer cells and the enrichment of ZIP1⁺ fibroblasts. ZIP1⁺ fibroblasts interconnect cancer cells with gap junctions by upregulating CX43. Upon treatment, the ability of Zn²⁺ uptake by cancer cells is suppressed. ZIP1⁺ fibroblasts act as a reservoir to absorb and transfer Zn²⁺ to lung cancer cells via gap junctions. In ZIP1⁺ fibroblasts, imported Zn²⁺ stimulates degradation of PTEN and activation of AKT to upregulate the expression of gap junction protein CX43. In lung cancer cells, the elevation of Zn²⁺ enhances the expression of ABCB1 and reduces the accumulation of drugs, resulting in chemoresistance.