Le Bras, M. | bioRxiv Science

bioRxiv2024

Src promotes tumor cell invasion by hijacking the translation machinery

The Src oncogene controls cancer cell invasiveness by promoting invadosome formation and extracellular matrix degradation (ECM). Invadosomes are enriched in the eukaryotic translation initiation factor 3 (eIF3) complex associated with a local mRNA translation activity mandatory for their maintenance. Here, we show that Src regulates mRNA translation by controlling the expression of eIF3 subunits. Among them, eIF3h/e/d are essential for invadosome formation and ECM degradation. We demonstrate that Src controls the canonical mTOR/eIF4E and the non-canonical eIF3d cap-dependent translation initiation pathways. We show that both pathways are necessary for invadosome formation and their ECM degradation function. Finally, we highlighted a correlation between Src and eIF3h/e/d overexpression, which is associated with poor prognosis in hepatocellular carcinoma (HCC) patients and controls the ECM degradation and invasive properties of HCC cells. These findings identify Src as a major regulator of translation initiation pathways, which leads to invadosome formation, ECM degradation and tumor cell invasion. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/606119v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1804203org.highwire.dtl.DTLVardef@16ddae8org.highwire.dtl.DTLVardef@13ecca5org.highwire.dtl.DTLVardef@1ed685a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cell biology↗

bioRxiv2023

Default Values And Read-Across Proposal For Dermal Absorption Based On Human Skin In Vitro Studies Dataset With Pesticides

The skin is the main route of exposure to plant protection products for operators, workers, residents, and bystanders. Assessing dermal absorption is key for evaluating pesticide exposure. The initial approach to risk assessment involves using default dermal absorption values or applying read-across data from experimental results from different formulations. In this way, to support non-dietary pesticide risk assessment focused but not limited to Brazil, this project evaluated 759 GLP-compliant in vitro human skin dermal absorption studies covering 25 formulation types and 248 active substances at multiple concentrations using interpretable machine learning techniques. Bayesian Additive Regression Trees - BART method indicated that Log Pow and molecular weight have the highest importance when predicting dermal absorption; both parameters exhibit moderate interaction uncertainty within each other and with formulation groups water-based and organic-solvent based and with tested form (concentrates or dilutions). The default values for each formulation group were determined using the upper bound of a non-parametric confidence interval for a specified quantile, with calculations conducted via bootstrapping methods; the proposed values correspond to the upper limit of the 95% confidence interval for the 95th percentile: for concentrates, 10% for organic-solvent based, 4% for water-based and 3% for solid formulations. For dilutions, 42% for organic-solvent based, 37% for water-based and 39% for solid formulations. Organic-solvent based dermal absorption values from experimental data can be used as conservative surrogates for solid and water-based formulations. When no experimental data is available for higher spray dilutions of a given formulation type, a pro-rated correction is proposed to a 2 to 5-fold concentration difference, limited to the respective formulation group default value.

pharmacology and toxicology↗