A more physiological approach to lipid metabolism alterations in cancer: CRC-like organoids assessment

Precision medicine might be the response to the recent questioning of the use of metformin as an anticancer drug in colorectal cancer (CRC). Thus, in order to establish properly its benefits, its application need to be assayed on the different progression stages of CRC. In this way, organoids imply a more physiological tool, representing a new therapeutic opportunity for CRC personalized treatment to assay tumor stage-dependent drugs effects. Since the lipid metabolism-related axis, ACSL/SCD, stimulates colon cancer progression and Metformin is able to rescuing the invasive and migratory phenotype conferred to cancer cells upon this axis overexpression; we checked ACSL/SCD status, its regulatory miRNAs and the effect of Metformin treatment in organoids as a model for specific and personalized treatment. Despite ACSL4 expression is upregulated in CRC-like organoids, Metformin is able to downregulate it, especially in the first stages. Besides, organoids are clearly more sensitive in this first stage (Apc mutated) to Metformin than current chemotherapeutic drugs such as fluorouracil (5-FU). Metformin performs an independent “Warburg effect” blockade to cancer progression and is able to reduce crypt stem cell markers expression such as Lgr5+. These results suggest a putative increased efficiency of the use of Metformin in the first stages of CRC than in advanced disease. Abbreviations : ACSL1 : Acyl-CoA synthetase 1 ACSL4 : Acyl-CoA synthetase 4 CRC : Colorectal cancer EMT : Epithelial-mesenchymal transition 5-FU : Fluorouracil MiRNAs/ miR : MicroRNAs MTT : 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide OAA : Oxaloacetate SCD : Stearoyl-CoA desaturase TCA : Tricarboxylic Acid cycle 2D : 2-dimensional 3D : 3-dimensional.