Reprogramming of mitochondrial metabolism in the CMS subtypes of colon cancer

L’attribut alt de cette image est vide, son nom de fichier est Fatima.png.

A recent and major improvement in colorectal cancer (CRC) arises from the classification of most tumors into one of four consensus molecular subtypes (CMS1 to CMS4), the CMS4 subtype having the worst prognosis. This new categorization, based on transcriptional profiles, allows significant improvements in the stratification of patients and is now considered as the gold standard for the clinical management of CRC. However, many fundamental aspects remain to be explored. In particular, still little is known on the molecular and metabolic pathways underlying the specificities of the various CMS subtypes. Indeed, ascribing a specific metabolic signature to each CMS subgroup could improve CRC diagnosis, and could contribute to identify new therapeutic targets, and/or to predict response to chemotherapy.

The research on cancer metabolism has long been focused almost exclusively on glycolysis, and amino acid/fatty acids synthesis, and the relevance of mitochondrial energy metabolism for oncogenesis/tumor progression in colorectal cancer has only been marginally studied.

Thus, the aim of our group is to gain a better understanding of the metabolic signature of CMS subtypes with a particular focus on mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC), pathways that have been overlooked for many years. A more comprehensive characterization of the metabolic landscape of CMS subtypes of colorectal cancer could participate to identify potential therapeutic targets. To do so, we will mine into the deep knowledge and experience gained during the past decades dedicated to study the regulation of mitochondrial functions and the pharmacological correction of inherited FAO or RC disorders, which form a large family of rare diseases.

Our research, associating cellular, molecular and biochemical approaches, aims at characterizing the expression of FAO and RC, and the roles of several key cellular signaling pathways (via PPAR, PGC-1alpha, AMPK, Sirtuins…) in the reprogramming of mitochondrial energy metabolism in the various CMS subtypes. This should allow to identify key mitochondrial enzymes and their associated signaling pathways that can be targeted by pharmacological approaches, using drugs or natural compounds, and thus open new avenues for the treatment of CRC.

Publications
Boufroura FZ, Tomkiewicz-Raulet C, Poindessous V, Castille J, Vilotte JL, Bastin J, Mouillet-Richard S, Djouadi F. Cellular prion protein dysfunction in a prototypical inherited metabolic myopathy. Cell. Mol.Life.Sci. 2020, Sep 1. doi: 10.1007/s00018-020-03624-6

Bastin J, Djouadi F. Dysfunctions of mitochondrial fatty acid b-oxidation in rare and common diseases. Med Sci (Paris). 2019 Oct;35(10):779-786. doi: 10.1051/medsci/2019156. Epub 2019 Oct 18. French.

Djouadi F, Bastin J. Mitochondrial genetics disorders: cell signaling and pharmacological therapies. Cells. 2019 Mar 28;8(4). pii: E289. doi: 10.3390/cells8040289.

Boufroura FZ, Le Bachelier C, Tomkiewicz-Raulet C, Schlemmer D, Benoist JF, Grondin P, Lamotte Y, Mirguet O, Bastin J, Djouadi F. A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defects in CPT2-deficient myotubes. Hum. Mol. Genet. 2018, 27: 3417-3433