Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age-related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer.

A key step of epithelial morphogenesis is the creation of the lumen. Luminogenesis by hollowing proceeds through the fusion of apical vesicles at cell-cell contacts. The small nascent lumens grow through extension, coalescence and enlargement, coordinated with cell division, to give rise to a single central lumen. Here, by using MDCK cells grown in 3D-culture, we show that EFA6A (also known as PSD) participates in luminogenesis. EFA6A recruits α-actinin 1 (ACTN1) through direct binding. In polarized cells, ACTN1 was found to be enriched at the tight junction where it acts as a primary effector of EFA6A for normal luminogenesis. Both proteins are essential for the lumen extension and enlargement, where they mediate their effect by regulating the cortical acto-myosin contractility. Finally, ACTN1 was also found to act as an effector for the isoform EFA6B (also known as PSD4) in the human mammary tumoral MCF7 cell line. EFA6B restored the glandular morphology of this tumoral cell line in an ACTN1-dependent manner. Thus, we identified new regulators of cyst luminogenesis essential for the proper maturation of a newly-formed lumen into a single central lumen.

Breast cancer is a major disease for women worldwide, where mortality is associated with tumour cell dissemination to distant organs. While the number of efficient anticancer therapies increased in the past 20 years, treatments targeting the invasive properties of metastatic tumour cells are still awaited. Various studies analysing invasive breast cancer cell lines have demonstrated that Arf6 is an important player of the migratory and invasive processes. These observations make Arf6 and its regulators potential therapeutic targets. As of today, no drug effective against Arf6 has been identified, with one explanation being that the activation of Arf6 is dependent on the presence of lipid membranes that are rarely included in drug screening. To overcome this issue we have set up a fluorescence-based high throughput screening that follows overtime the activation of Arf6 at the surface of lipid membranes. Using this unique screening assay, we isolated several compounds that affect Arf6 activation, among which the antibiotic chlortetracycline (CTC) appeared to be the most promising. In this report, we describe CTC in vitro biochemical characterization and show that it blocks both the Arf6-stimulated collective migration and cell invasion in a 3D collagen I gel of the invasive breast cancer cell line MDA-MB-231. Thus, CTC appears as a promising hit to target deadly metastatic dissemination and a powerful tool to unravel the molecular mechanisms of Arf6-mediated invasive processes.