Corne d’abondance

La société Hi-bred International du Zimbabwe a mis au point deux nouvelles variétés de maïs capables de résister à la redoutable maladie des taches grises. Des tests conduits dans de petites et grandes exploitations ont confirmé le rendement élevé de ces variétés (9 à 11t/ha), qui peuvent être transformées localement et ne nécessitent pas plus d’engrais que les autres variétés. Elles sont distribuées au Malawi par Chemicals and Marketing Malawi Limited qui organise des démonstrations.La société Hi-bred International du Zimbabwe a mis au point deux nouvelles variétés de maïs capables de résister à la redoutable maladie des taches grises. Des tests conduits dans de petites et grandes exploitations ont confirmé le rendement..

MOESM3 of Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases

Additional file 3: Figure S2. Complement and coagulation cascades (A) are enriched in good responder. Cell adhesion molecules (B), calcium signaling pathway (C) and MAPK signaling pathway (D) are highly enriched and up-regulated in poor responder, as visualized by GSEA

MOESM5 of Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases

Additional file 5: Figure S3. Correlation of proteins (P62937, P61962, Q6FI81, P21266) identified by nearest shrunken centroid and CPL/MUW proteome database, including 255 cell cultures, cell states and tissue, leading to a high protein similarity to the resistant melanoma cell line TMFI

MOESM1 of Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases

Additional file 1: Figure S1. Study outline shows the experimental design of the study

MOESM2 of Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases

Additional file 2: Table S1. Clinical table with age, gender, treatment, response distribution, PFS, mutational status, all number of samples, IC50 of the cell systems and the applied methods

Proteomic identification of a marker signature for MAPKi resistance in melanoma

ISSN:0261-4189ISSN:1460-207

Proteomic identification of a marker signature for MAPKi resistance in melanoma

MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. The ability of melanoma cells to switch from melanocytic to mesenchymal phenotypes appears to be associated with therapeutic resistance. High-throughput, subcellular proteome analyses and RNAseq on two panels of primary melanoma cells that were either sensitive or resistant to MAPKi revealed that only 15 proteins were sufficient to distinguish between these phenotypes. The two proteins with the highest discriminatory power were PTRF and IGFBP7, which were both highly upregulated in the mesenchymal-resistant cells. Proteomic analysis of CRISPR/Cas-derived PTRF knockouts revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFβ signalling and cell migration and adhesion, as well as a significantly reduced invasive index and ability to form spheres in 3D culture. Overexpression of PTRF led to MAPKi resistance, increased cell adhesion and sphere formation. In addition, immunohistochemistry of patient samples showed that PTRF expression levels were a significant biomarker of poor progression-free survival, and IGFBP7 levels in patient sera were shown to be higher after relapse

ROS induction as a strategy to target persister cancer cells with low metabolic activity in NRAS mutated melanoma

Metabolic reprogramming is an emerging hallmark of resistance to cancer therapy but may generate vulnerabilities that can be targeted with small molecules. Multi-omics analysis revealed that NRAS-mutated melanoma cells with a mesenchymal transcriptional profile adopt a quiescent metabolic program to resist cellular stress response induced by MEK-inhibitor resistance. However, as a result of elevated baseline ROS levels, these cells become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intra-tumor heterogeneity requires the combination of a ROS-inducer and a MEK-inhibitor to target both tumor growth and metastasis. By ex vivo pharmacoscopy of 62 human metastatic melanomas, we found that MEK-inhibitor resistant tumors significantly benefitted from the combination therapy. Finally, we profiled 486 cancer cell lines and revealed that oxidative stress responses and translational suppression are biomarkers of ROS-inducer sensitivity, independent of cancer indication. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS-inducers in melanoma and other cancers. Statement of Significance Targeted-therapy resistance in cancer arises from genetic selection and both transcriptional and metabolic adaptation. We show that metabolic reprogramming sensitizes resistant cells to ROS-induction in combination with pathway inhibitors. Predictive biomarkers of metabolic sensitivity to ROS-inducing agents were identified in many cancer entities, highlighting the generalizability of this treatment approach

ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma

Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers. Significance: Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors