SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Gut Année : 2023

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

Raphael Rapetti-Mauss
Olivier Soriani

Résumé

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 (KIC pdx1 ) 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.
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hal-04257740 , version 1 (25-10-2023)

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Raphael Rapetti-Mauss, Jérémy Nigri, Camille Berenguier, Pascal Finetti, Sarah Simha Tubiana, et al.. SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer. Gut, 2023, 72 (4), pp.722-735. ⟨10.1136/gutjnl-2021-326610⟩. ⟨hal-04257740⟩
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