RT Journal Article
SR Electronic
T1 SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 722
OP 735
DO 10.1136/gutjnl-2021-326610
VO 72
IS 4
A1 Raphael Rapetti-Mauss
A1 Jérémy Nigri
A1 Camille Berenguier
A1 Pascal Finetti
A1 Sarah Simha Tubiana
A1 Bonnie Labrum
A1 Benoit Allegrini
A1 Bernard Pellissier
A1 Georgios Efthymiou
A1 Zainab Hussain
A1 Corinne Bousquet
A1 Nelson Dusetti
A1 François Bertucci
A1 Hélène Guizouarn
A1 Patricia Melnyk
A1 Franck Borgese
A1 Richard Tomasini
A1 Olivier Soriani
YR 2023
UL http://gut.bmj.com/content/72/4/722.abstract
AB 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.Data are available in a public, open access repository.