An integrin centered complex coordinates ion transport and pH to regulate f-actin organization and cell migration in breast cancer

The cross talk between the Microenvironment (TME) and cancer cells controls proliferation, migration and pro-metastatic cancer behavior, often through integrin-mediated cell adhesion to the Extracellular Matrix (ECM). Integrin receptors coordinate signaling hubs constituted by multiprotein plasma membrane complexes often comprising ion channels and transporters. We here describe a novel signaling pathway triggered by (1 integrin activation by the ECM protein fibronectin (FN). This pathway involves a (1 integrin-centered plasma membrane complex formed by different transport proteins: the hERG1 K ⁺ channel, the neonatal form of the Na ⁺ channel NaV 1.5 (nNaV1.5) and the Na ⁺ /H ⁺ antiporter NHE1. The NHE1/hERG1/(1/nNaV1.5 complex is present on the plasma membrane of Breast Cancer (BCa) cells, in particular Triple Negative Breast Cancer (TNBCa). The expression of the two ion channels present in the complex is mutually regulated. The complex engagement by cell adhesion to FN stimulates a NHE1-mediated cytoplasmic alkalinization, which modulates f-actin organization. This in turn controls TNBCa migration and invasiveness. All this pathway is impaired by blocking either hERG1 or nNaV1.5 which also cause complex disassembly. The same result is obtained by harnessing the hERG1/(1 integrin complex through a single chain bispecific antibody (scDb-hERG1-(1).

In conclusion, we uncovered a plasma membrane complex that recruits different ion transport proteins that regulate cellular K ⁺ , Na ⁺ and H ⁺ fluxes and cooperate in modulating downstream signals and thus malignant behavior. This complex could be targeted to develop novel therapeutic strategies for one of the most difficult-to-treat cancers, i.e. TNBCa.