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

胰腺癌 转移 癌症研究 生物 间质细胞 癌细胞 癌症 蛋白激酶B 细胞生物学 信号转导 遗传学
作者
Raphael Rapetti‐Mauss,Jérémy Nigri,Camille Berenguier,Pascal Finetti,Sarah-Simha Tubiana,Bonnie Labrum,Benoit Allegrini,Bernard Pellissier,Georgios Efthymiou,Zainab Hussain,Corinne Bousquet,Nelson Dusetti,François Bertucci,Hélène Guizouarn,Patricia Melnyk,Franck Borgèse,Richard Tomasini,Olivier Soriani
出处
期刊:Gut [BMJ]
卷期号:72 (4): 722-735 被引量:12
标识
DOI:10.1136/gutjnl-2021-326610
摘要

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. 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. 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). 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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