Cell competition promotes metastatic intestinal cancer through a multistage process.

Cell competition plays an instrumental role in quality control during tissue development and homeostasis. Nevertheless, cancer cells can exploit this process for their own proliferative advantage. In our study, we generated mixed murine organoids and microtissues to explore the impact of cell competition on liver metastasis. Unlike competition at the primary site, the initial effect on liver progenitor cells does not involve the induction of apoptosis. Instead, metastatic competition manifests as a multistage process. Initially, liver progenitors undergo compaction, which is followed by cell-cycle arrest, ultimately forcing differentiation. Subsequently, the newly differentiated liver cells exhibit reduced cellular fitness, rendering them more susceptible to outcompetition by intestinal cancer cells. Notably, cancer cells leverage different interactions with different epithelial populations in the liver, using them as scaffolds to facilitate their growth. Consequently, tissue-specific mechanisms of cell competition are fundamental in driving metastatic intestinal cancer.

Sustained Nrf2 Overexpression-Induced Metabolic Deregulation Can Be Attenuated by Modulating Insulin/Insulin-like Growth Factor Signaling.

The modulation of insulin/insulin-like growth factor signaling (IIS) is associated with altered nutritional and metabolic states. The Drosophila genome encodes eight insulin-like peptides, whose activity is regulated by a group of secreted factors, including Ecdysone-inducible gene L2 (ImpL2), which acts as a potent IIS inhibitor. We recently reported that cncC (cncC/Nrf2), the fly ortholog of Nrf2, is a positive transcriptional regulator of ImpL2, as part of a negative feedback loop aiming to suppress cncC/Nrf2 activity. This finding correlated with our observation that sustained cncC/Nrf2 overexpression/activation (cncCOE; a condition that signals organismal stress) deregulates IIS, causing hyperglycemia, the exhaustion of energy stores in flies' tissues, and accelerated aging. Here, we extend these studies in Drosophila by assaying the functional implication of ImpL2 in cncCOE-mediated metabolic deregulation. We found that ImpL2 knockdown (KD) in cncCOE flies partially reactivated IIS, attenuated hyperglycemia and restored tissue energetics. Moreover, ImpL2 KD largely suppressed cncCOE-mediated premature aging. In support, pharmacological treatment of cncCOE flies with Metformin, a first-line medication for type 2 diabetes, restored (dose-dependently) IIS functionality and extended cncCOE flies' longevity. These findings exemplify the effect of chronic stress in predisposition to diabetic phenotypes, indicating the potential prophylactic role of maintaining normal IIS functionality.

Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia.

SPG15 is a hereditary spastic paraplegia subtype caused by mutations in Spastizin, a protein encoded by the ZFYVE26 gene. Spastizin is involved in autophagosome maturation and autophagic lysosome reformation and SPG15-related mutations lead to autophagic lysosome reformation defects with lysosome enlargement, free lysosome depletion and autophagosome accumulation. Symptomatic and rehabilitative treatments are the only therapy currently available for patients. Here, we targeted autophagy and lysosomes in SPG15 patient-derived cells by using a library of autophagy-modulating compounds. We identified a rose of compounds affecting intracellular calcium levels, the calcium-calpain pathway or lysosomal functions, which reduced autophagosome accumulation. The six most effective compounds were tested in vivo in a new SPG15 loss of function Drosophila model that mimicked the reported SPG15 phenotype, with autophagosome accumulation, enlarged lysosomes, reduced free lysosomes, autophagic lysosome reformation defects and locomotor deficit. These compounds, namely verapamil, Bay K8644, 2',5'-dideoxyadenosine, trehalose, Small-Molecule Enhancer of Rapamycin 28 and trifluoperazine, improved lysosome biogenesis and function in vivo, demonstrating that lysosomes are a key pharmacological target to rescue SPG15 phenotype. Among the others, the Small-Molecule Enhancer of Rapamycin 28 was the most effective, rescuing both autophagic lysosome reformation defects and locomotor deficit, and could be considered as a potential therapeutic compound for this hereditary spastic paraplegia subtype.

Evolution of Internet addiction in Greek adolescent students over a two-year period: the impact of parental bonding.

We present results from a cross-sectional study of the entire adolescent student population aged 12-18 of the island of Kos and their parents, on Internet abuse, parental bonding and parental online security practices. We also compared the level of over involvement with personal computers of the adolescents to the respective estimates of their parents. Our results indicate that Internet addiction is increased in this population where no preventive attempts were made to combat the phenomenon from the initial survey, 2 years ago. This increase is parallel to an increase in Internet availability. The best predictor variables for Internet and computer addiction were parental bonding variables and not parental security practices. Parents tend to underestimate the level of computer involvement when compared to their own children estimates. Parental safety measures on Internet browsing have only a small preventive role and cannot protect adolescents from Internet addiction. The three online activities most associated with Internet addiction were watching online pornography, online gambling and online gaming.