The crosstalk between the tumour microenvironment (TME) and cancer cells: the role of ion channels.

The tumour microenvironment (TME) is a dynamic and intricate network of cells and molecules that evolves in response to cancer invasion, influencing tumour biology and treatment responses. This study investigates the role of ion channels, particularly hERG1, in the communication between cancer cells and the TME. We elucidate a mechanistic pathway involving hERG1 interaction with the β1 integrin receptor, unveiling its profound impact on cell migration, response to mechanical stimuli, and stroma interaction. Our findings reveal that integrin engagement triggers a biphasic response in hERG1 ion channels. Initial stimulation leads to the translocation of hERG1 channels to the plasma membrane, resulting in increased current amplitude and membrane hyperpolarization. Subsequently, hERG1 forms a complex with integrin, maintaining a closed conformation on the plasma membrane, which gradually restores the initial state. This hERG1/β1 integrin complex, modulated by the Gαi3 signalling pathway, significantly influences cancer cell migration and response to mechanical cues, in part due to its impact on cytoskeletal elements like cortical f-actin. In addition, we demonstrate the role of hERG1 in mediating the response of cancer cells to changes in extracellular matrix stiffness, implicating YAP mechanotransduction. This connection adds to the growing understanding of the role of mechanotransduction in cancer progression and supports the potential for targeted therapies in this context. Overall, this research provides crucial insights into the complex interplay between ion channels, the TME, and cancer cells, offering new avenues for anti-metastatic strategies and personalized treatment approaches in the field of oncology. The mechanistic insights provided by our findings, indeed, suggest the potential for targeting hERG1 and β1 integrin interaction during the initial phases of cancer cell migration as an anti-metastatic strategy. This approach may offer therapeutic benefits without affecting hERG1 function in non-cancerous tissues, thus circumventing cardiotoxic side effects associated with hERG1 blockers. Our results also highlight the potential use of Ectica plates for conducting preclinical research and personalized treatment in patient-derived primary cultures