Ffar2 expression regulates leukaemic cell growth in vivo Laure B Bindels 1 , Paolo E Porporato 2,3 , Sarah Ducastel 4 , Martina Sboarina 2 , Audrey M Neyrinck 1 , Evelyne M Dewulf 1 , Olivier Feron 2 , Sophie Lestavel 4 , Patrice D Cani 1,5 , Bart Staels 4 , Pierre Sonveaux 2 and Nathalie M Delzenne * ,1 1 Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Universite ´ Catholique de Louvain, Avenue Mounier 73, Box B1.73.11, Brussels 1200, Belgium; 2 Pole of Pharmacology, Institut de Recherche Expe ´ rimentale et Clinique (IREC), Universite ´ Catholique de Louvain, Avenue Mounier 52, Box B1.53.09, Brussels 1200, Belgium; 3 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy; 4 European Genomic Institute for Diabetes (EGID), Universite ´ Lille, INSERM UMR 1011, Institut Pasteur de Lille, CHU de Lille, Rue du Professeur Calmette 1, Lille F-59019, France and 5 Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Louvain Drug Research Institute, UCL, Brussels B-1200, Belgium Background: Activation of free fatty acid receptor 2 (FFAR2) by microbiota-derived metabolites (e.g., propionate) reduces leukaemic cell proliferation in vitro. This study aims to test whether Ffar2 expression per se also influences leukaemia cell growth in vivo. Methods: Bcr-Abl-expressing BaF cells were used as a leukaemia model and the role of Ffar2 was evaluated in Balb/c mice after lentiviral shRNA transduction. Results: Our data formally establish that reduced leukaemic cell proliferation is associated with increased Ffar2 expression in vivo and in vitro. Going beyond association, we point out that decreasing Ffar2 expression fosters cancer cell growth in vitro and in vivo. Conclusions: Our data demonstrate the role of Ffar2 in the control of leukaemic cell proliferation in vivo and indicate that a modulation of Ffar2 expression through nutritional tools or pharmacological agents may constitute an attractive therapeutic approach to tackle leukaemia progression in humans. Short-chain fatty acids (SCFA), such as acetate, propionate and butyrate, are microbial byproducts of fermentation that are involved in the gut microbiota–host crosstalk through several pathways (Bindels et al, 2013; Canfora et al, 2015). Free fatty acid receptor 2 (FFAR2), also known as GPR43 or FFA2, is a G-protein coupled receptor that binds propionate. Its activation reduces leukaemic cell proliferation in vitro (Bindels et al, 2013). In a mouse model of leukaemia consisting in the transplantation of Bcr- Abl-transfected BaF cells, feeding inulin-type fructans (ITF), a non-digestible fermentable fiber changing the gut microbiota, leads to increased portal propionate levels and reduced hepatic leukaemic cell proliferation (Bindels et al, 2012). We and others have documented that beside the canonical histone deacetylase pathway, the FFAR2 pathway could also mediate the anti-proliferative effect of SCFA such as propionate (Tang et al, 2011; Bindels et al, 2012; Shi et al, 2014). While overexpression of Ffar2 induces apoptosis (Tang et al, 2011; Shi et al, 2014), our data reveal that its knocking down increases the growth of leukaemic cells in vivo. MATERIALS AND METHODS Chemicals. All chemicals were purchased from Sigma-Aldrich (St Louis, MO, USA), except CMTB [4-chloro-a-(1-methylethyl)- N-2-thiazolyl-benzeneacetamide] (Ambinter, Paris, France) and imatinib mesylate (Cayman Chemical, Tallinn, Estonia). *Correspondence: Professor NM Delzenne; E-mail: nathalie.delzenne@uclouvain.be Revised 21 June 2017; accepted 8 August 2017; published online 5 September 2017 r The Author(s) named above SHORT COMMUNICATION Keywords: cell proliferation; CMTB; free fatty acid receptor; FFA2; GPR43; leukaemic cells; propionate; short-chain fatty acids British Journal of Cancer (2017) 117, 1336–1340 | doi: 10.1038/bjc.2017.307 1336 Published by Springer Nature on behalf of Cancer Research UK.