Regulation of ion channels in cancer
- Understanding how ion channels participate to the functional heterogeneity of the cancer tissue
- Understanding the role of ion channels in the dysregulation of cancer-associated signaling pathways
- Finding ion channel-associated targets to reduce tumour invasiveness
- Defining the physiopathological mechanisms associated to ion channel mutations in red blood cells
Ion channels are membrane proteins involved in many physiological and pathophysiological processes. Our group has focused his research on the role of these membrane proteins in cancer and hereditary hemolytic anemias.
1) Ion channel and cancer: Ion channels are involved in coupling extracellular events to cell behaviour. They contribute to the hallmarks of cancers and clinical outcome. Therefore, it is crucial to gain knowledge on the oncogenic mechanisms behind ion channel dysregulation to enhance current treatments.
2) Hereditary stomatocytosis is responsible for hemolytic anemia that is caused by mutations in red blood cell ion channels. Understanding ion channel alterations behing mutations in patients is a prerequisite to treat this rare disease.
1) Using 3D cell culture, co-culture with cell lines specifically expressing or invalidated for targetted ion channels and their regulators, we study the impact of various components of the tumour micro environmment (TME) (such as cancer fibroblast-derived matrix) on tumour cell electrical activity, as well as the link between ion channel activity and tumour cell behavior in vitro and in vivo. This led to the characterization of several ion channels and regulatory proteins as potential players in TME-induced cancer cell invasiveness.
2) By organizing a partnership with Hematologists, we characterize the different mutations identified in patients suffering hereditary stomatocytosis. The moleculars features of mutated ion channels are studied as well as their effect on red blood cell homeostasis.
In the last few years, the study of the tumour microenvironment has taken a significant place in the field of cancer research. We have shown that SigmaR1, a stress-activated ion channel chaperone, plays a key function by controlling ion channels in response to TME. Therefore, We aim at characterizing the network of ion channels controlled by SigmaR1 in cancer cells and its functions in metastasic process in vivo and in vitro.
SigmaR1 is considered as a potential pharmacological target in neurodegenerative diseases and cancer. However, the molecular mechanisms underlying the coupling between SigmaR1 and ion channels need to be characterized to develop drugs modulating this interaction. By combining electrophysiology, biochemistry and imagery we aim at defining the dynamics of interaction between the partners, and the way sigma ligands interfere with SigmaR1/ion channel complexes.
At the moment, two different genes have been linked to the dehydrated form of hereditary stomatocytosis: KCNN4 coding for the Gardos channel (our work) and Piezo1 coding for a mechano-sensitive ion channel. We aim at a better understanding of the connection between these two ion channels to develop treatments for this pathology as well as for other red blood cell pahtologies where volume homeostasis is impaired.
- Rapetti-Mauss, R, Borgese, F, Harvey, BJ, Soriani, O. [KCNQ1: a new regulator of the epithelio-mesenchymal transition in colorectal cancers]. Med Sci (Paris). 2018;34 (1):21-24. doi: 10.1051/medsci/20183401006. PubMed PMID:29384089 .
- Rapetti-Mauss, R, Picard, V, Guitton, C, Ghazal, K, Proulle, V, Badens, C et al.. Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis. Haematologica. 2017;102 (10):e415-e418. doi: 10.3324/haematol.2017.171389. PubMed PMID:28619848 PubMed Central PMC5622875.
- Rapetti-Mauss, R, Bustos, V, Thomas, W, McBryan, J, Harvey, H, Lajczak, N et al.. Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation. Proc. Natl. Acad. Sci. U.S.A. 2017;114 (16):4159-4164. doi: 10.1073/pnas.1702913114. PubMed PMID:28373572 PubMed Central PMC5402468.
- Soriani, O, Rapetti-Mauss, R. Sigma 1 Receptor and Ion Channel Dynamics in Cancer. Adv. Exp. Med. Biol. 2017;964 :63-77. doi: 10.1007/978-3-319-50174-1_6. PubMed PMID:28315265 .
- Rapetti-Mauss, R, Soriani, O, Vinti, H, Badens, C, Guizouarn, H. Senicapoc: a potent candidate for the treatment of a subset of hereditary xerocytosis caused by mutations in the Gardos channel. Haematologica. 2016;101 (11):e431-e435. doi: 10.3324/haematol.2016.149104. PubMed PMID:27443288 PubMed Central PMC5394861.
- Guéguinou, M, Harnois, T, Crottes, D, Uguen, A, Deliot, N, Gambade, A et al.. SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline. Oncotarget. 2016;7 (24):36168-36184. doi: 10.18632/oncotarget.8786. PubMed PMID:27102434 PubMed Central PMC5094991.
- Crottès, D, Félix, R, Meley, D, Chadet, S, Herr, F, Audiger, C et al.. Immature human dendritic cells enhance their migration through KCa3.1 channel activation. Cell Calcium. 2016;59 (4):198-207. doi: 10.1016/j.ceca.2016.02.008. PubMed PMID:27020659 .
- Crottès, D, Rapetti-Mauss, R, Alcaraz-Perez, F, Tichet, M, Gariano, G, Martial, S et al.. SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness. Cancer Res. 2016;76 (3):607-18. doi: 10.1158/0008-5472.CAN-15-1465. PubMed PMID:26645564 .
- Rapetti-Mauss, R, Lacoste, C, Picard, V, Guitton, C, Lombard, E, Loosveld, M et al.. A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood. 2015;126 (11):1273-80. doi: 10.1182/blood-2015-04-642496. PubMed PMID:26148990 .
- Balasuriya, D, D'Sa, L, Talker, R, Dupuis, E, Maurin, F, Martin, P et al.. A direct interaction between the sigma-1 receptor and the hERG voltage-gated K+ channel revealed by atomic force microscopy and homogeneous time-resolved fluorescence (HTRF®). J. Biol. Chem. 2014;289 (46):32353-63. doi: 10.1074/jbc.M114.603506. PubMed PMID:25266722 PubMed Central PMC4231707.
- Crottès, D, Guizouarn, H, Martin, P, Borgese, F, Soriani, O. The sigma-1 receptor: a regulator of cancer cell electrical plasticity?. Front Physiol. 2013;4 :175. doi: 10.3389/fphys.2013.00175. PubMed PMID:23882221 PubMed Central PMC3712323.
- Balasuriya, D, Stewart, AP, Crottès, D, Borgese, F, Soriani, O, Edwardson, JM et al.. The sigma-1 receptor binds to the Nav1.5 voltage-gated Na+ channel with 4-fold symmetry. J. Biol. Chem. 2012;287 (44):37021-9. doi: 10.1074/jbc.M112.382077. PubMed PMID:22952230 PubMed Central PMC3481303.
- Crottès, D, Martial, S, Rapetti-Mauss, R, Pisani, DF, Loriol, C, Pellissier, B et al.. Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells. J. Biol. Chem. 2011;286 (32):27947-58. doi: 10.1074/jbc.M111.226738. PubMed PMID:21680736 PubMed Central PMC3151040.
- Le Guennec, JY, Ouadid-Ahidouch, H, Soriani, O, Besson, P, Ahidouch, A, Vandier, C et al.. Voltage-gated ion channels, new targets in anti-cancer research. Recent Pat Anticancer Drug Discov. 2007;2 (3):189-202. . PubMed PMID:18221062 .
- Martial, S, Giorgelli, JL, Renaudo, A, Derijard, B, Soriani, O. SP600125 inhibits Kv channels through a JNK-independent pathway in cancer cells. Biochem. Biophys. Res. Commun. 2008;366 (4):944-50. doi: 10.1016/j.bbrc.2007.12.027. PubMed PMID:18082627 .
- Renaudo, A, L'Hoste, S, Guizouarn, H, Borgèse, F, Soriani, O. Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Cl- channels. J. Biol. Chem. 2007;282 (4):2259-67. doi: 10.1074/jbc.M607915200. PubMed PMID:17121836 .
- Renaudo, A, Watry, V, Chassot, AA, Ponzio, G, Ehrenfeld, J, Soriani, O et al.. Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kip1 accumulation. J. Pharmacol. Exp. Ther. 2004;311 (3):1105-14. doi: 10.1124/jpet.104.072413. PubMed PMID:15277583 .
2013 - Prime d'Excellence Scientifique - Université Nice Sophia Antipolis
iBV - Institut de Biologie Valrose
Université Nice Sophia Antipolis
Faculté des Sciences
06108 Nice cedex 2