SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer

Objective Intercellular communication within pancreatic ductal adenocarcinoma (PDAC) dramatically contributes to metastatic processes. The underlying mechanisms are poorly understood, resulting in a lack of targeted therapy to counteract stromal-induced cancer cell aggressiveness. Here, we investigated whether ion channels, which remain understudied in cancer biology, contribute to intercellular communication in PDAC. Design We evaluated the effects of conditioned media from patient-derived cancer-associated fibroblasts (CAFs) on electrical features of pancreatic cancer cells (PCC). The molecular mechanisms were deciphered using a combination of electrophysiology, bioinformatics, molecular and biochemistry techniques in cell lines and human samples. An orthotropic mouse model where CAF and PCC were co-injected was used to evaluate tumour growth and metastasis dissemination. Pharmacological studies were carried out in the Pdx1-Cre, Ink4a(fl/fl) LSL-Kras(G12D) (KICpdx1) mouse model. Results We report that the K+ channel SK2 expressed in PCC is stimulated by CAF-secreted cues (8.84 vs 2.49 pA/pF) promoting the phosphorylation of the channel through an integrin-epidermal growth factor receptor (EGFR)-AKT (Protein kinase B) axis. SK2 stimulation sets a positive feedback on the signalling pathway, increasing invasiveness in vitro (threefold) and metastasis formation in vivo. The CAF-dependent formation of the signalling hub associating SK2 and AKT requires the sigma-1 receptor chaperone. The pharmacological targeting of Sig-1R abolished CAF-induced activation of SK2, reduced tumour progression and extended the overall survival in mice (11.7 weeks vs 9.5 weeks). Conclusion We establish a new paradigm in which an ion channel shifts the activation level of a signalling pathway in response to stromal cues, opening a new therapeutic window targeting the formation of ion channel-dependent signalling hubs.

Automated summary

This study reveals that ion channel SK2 plays a role in intercellular communication in pancreatic ductal adenocarcinoma (PDAC). Stimulation of SK2 by cues from cancer-associated fibroblasts (CAFs) leads to the activation of the integrin-epidermal growth factor receptor (EGFR)-AKT signaling pathway, promoting cancer cell invasiveness and metastasis formation. The formation of the signaling hub involving SK2 and AKT requires the sigma-1 receptor chaperone. Targeting the sigma-1 receptor with pharmacological approaches inhibits tumor progression and prolongs overall survival in mice.