Gut 2022 September 1; Online First. doi: 10.1136/gutjnl-2021-326610

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

Raphael Rapetti-Mauss¹, Jérémy Nigri², Camille Berenguier¹, Pascal Finetti², Sarah Simha Tubiana², Bonnie Labrum¹, Benoit Allegrini¹, Bernard Pellissier¹, Georgios Efthymiou², Zainab Hussain², Corinne Bousquet³, Nelson Dusetti², François Bertucci², Hélène Guizouarn¹, Patricia Melnyk⁴, Franck Borgese¹, Richard Tomasini², Olivier Soriani¹

 

Affiliations
¹Université Côte d’azur, CNRS, Inserm, iBV, Nice, France
²INSERM, U1068, Cancer Research Center of Marseille, Institut Paoli-Calmettes, CNRS UMR7258, Université Aix-Marseille, Marseille, France
³Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM Unité Mixte de Recherche UMR-1037, CNRS Equipe de Recherche Labellisée ERL5294, Equipe de Recherche Labellisée “Ligue Contre le Cancer” & “LabEx Toucan”, Université de Toulouse, Toulouse, France
⁴Lille Neuroscience and Cognition Research Center UMR-S 1172, University of Lille, INSERM, CHU Lille, Lille, France

Abstract

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, Ink4afl/fl LSL-KrasG12D (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.

DOI: 10.1136/gutjnl-2021-326610