From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets

The analysis of human cancer by genome sequencing and various types of arrays has proved that many tumours harbour hundreds of genes that are mutated or substantially altered by copy number changes. But how many of these changes are meaningful? And how can we exploit these massive data sets to yield new targets for cancer treatment? In this Opinion article, we describe emerging approaches that aim to determine which altered genes are actually contributing to cancer, as well as their potential as therapeutic targets

Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice

International audienceThe endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease(1). Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of beta-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.

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The Enterokine Fibroblast Growth Factor 15/19 in Bile Acid Metabolism

The endocrine fibroblast growth factors (FGFs), FGF19, FGF21, and FGF23, play a key role in whole-body homeostasis. In particular, FGF19 is a postprandial hormone regulating glucose homeostasis, glycogen and protein synthesis, and primary bile acid (BA) metabolism. In the ileum, BA-dependent farnesoid X receptor (FXR) activation induces the production of FGF19, which reaches the liver through the portal system where it represses the expression of CYP7A1, the rate-limiting enzyme of hepatic de novo BAs synthesis. Dysregulation of BA levels associated with alteration in FGF19 level has been depicted in different pathological conditions of the gut-liver axis. Furthermore, FGF19 exploits strong anti-cholestatic and anti-fibrotic activities in the liver. However, native FGF19 seems to retain peculiar hepatic pro-tumorigenic actions. Recently engineered FGF19 analogues have been recently synthetized, with fully retained BA regulatory activity but without intrinsic pro-tumoral action, thus opening bona fide novel pharmacological strategy for the treatment of gut-liver axis diseases