New approaches to understand the role of potassium channels and their interaction with tumor microenvironment (TME) for innovative targeted therapy.

The formation of fibrotic tissue around tumor cells, known as desmoplasia, represents a significant challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). As a significant source of tumor-promoting cells within the extracellular matrix (ECM), stellate cells and cancer-associated fibroblasts (CAFs) represent a promising contributory factor in tumor development. The dysfunction and aberrant expression of ion channels is implicated in the pathogenesis of numerous diseases, including cancer, by mediating interactions between tumor cells and the tumor microenvironment (TME). The hERG1 (Kv 11.1) channel, which is aberrantly expressed in cancer cells, is co-expressed and interacts with β1 integrin. Furthermore, Kv 11.1 exerts an influence on PDAC cell migration through a complex interplay between the hERG1/β1 integrin and the girdin-dependent Gαi3. In this context, Kv 11.1 functions in a non-conductive manner, thereby altering the dynamics and organization of f-actin. It is noteworthy that PDAC cell lines exhibited heightened forces in response to increased stiffness, with this phenomenon exhibiting an inverse correlation with hERG1 and hERG1/β1 complex expression on the plasma membrane. This study investigates the role of the hERG1/β1 complex in different migration scenarios and its implication in YAP mechanotransduction. The mechanistic insights derived from our findings suggest that targeting the interaction between hERG1 and β1 integrin during the early stages of cancer cell migration may represent an effective anti-metastatic strategy. Indeed, potassium channels in a more physiologically relevant ECM microenvironment employing branching PDAC organoid models revealed a previously unidentified role for these channels in the interplay between plasticity and differentiation. The desmoplastic reaction and some of its key players, stellate cells and CAFs, lead to a PDAC cell's morphological and behavioral changes depending on its ratio. Our mixed orthotopic xenograft mouse model of PDAC pave the way for identifying new therapeutic targets and a reproducible translational research element for the development of innovative targeted combinations.