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Oncogenic signaling through the MAPK/ERK pathway drives tumor progression in many cancers. Although targeted MAPK/ERK pathway inhibitors improve survival in selected patients, most tumors are resistant. New drugs could be identified in small-animal models that, unlike in vitro models, can address oral uptake, compound bioavailability, and toxicity. This requires pharmacologic conformity between human and model MAPK/ERK pathways and available phenotypic assays. In this study, we test if the conserved MAPK/ERK pathway in Caenorhabditis elegans could serve as a model for pharmacological inhibition and develop in vivo pipelines for high-throughput compound screens. Using fluorescence-based image analysis of vulva development as a readout for MAPK/ERK activity, we obtained excellent assay Z-scores for the MEK inhibitors trametinib (Z = 0.95), mirdametinib (Z = 0.93), and AZD8330 (Z = 0.87), as well as the ERK inhibitor temuterkib (Z = 0.86). The throughput was 800 wells per hour, with an average seed density of 25.5 animals per well. Readouts included drug efficacy, toxicity, and pathway specificity, which was tested against pathway activating upstream (lin-15)- and downstream (lin-1) mutants. To validate the model in a high-throughput setting, we screened a blinded library of 433 anticancer compounds and identified four MEK inhibitors among seven positive hits. Our results highlight a high degree of pharmacological conformity between C. elegans and human MAPK/ERK pathways, and the presented high-throughput pipeline may discover and characterize novel inhibitors in vivo.
Pubmed ID: 39212544
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Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.
View all literature mentionsCaenorhabditis elegans with name lin-1(e1777) IV. from WB.
View all literature mentionsSoftware tool for multi level analysis of applications optimized for ImageXpress instruments. High-content image analysis software featuring time lapse analysis. Used for 2D and 3D imaging.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsImageXpress Micro Confocal system is a high-content solution that can switch between widefield and confocal imaging of fixed and live cells. It can capture high quality images of whole organisms, thick tissues, 2D and 3D models, and cellular or intracellular events. The spinning disc confocal and sCMOS camera enable imaging of fast and rare events like cardiac cell beating and stem cell differentiation. With MetaXpress software and flexible options like water immersion objectives to choose from, the system enables many confocal imaging applications from 3D assay development to screening.
View all literature mentionsPreset and manual controls for UV or time exposure settings. Internal microprocessor measures and controls UV output, ensuring maximum energy efficiency. Consistent crosslinking takes seconds with 8W shortwave UV tubes. Select shortwave for sterilization and bonding DNA; midrange for gel electrophoresis; or long wave for UV curing. Crosslinker has maximum energy setting of 999,900 �J/cm2. Uses five 8W UV tubes. Digital LED displays settings. Viewing window blocks UV while allowing visibility of chamber interior. An internal interlocking safety system is designed for automatic shutoff when the door is opened. 115V, 60Hz; ETL-/ETLc-certified. External dimensions (D x W x H) in. (cm): 13.7 x 15.6 x 8.75 (34.8 x 39.6 x 22.2).
View all literature mentionsSoftware tool to enable biologists without training in computer vision or programming to quantitatively measure phenotypes from thousands of images automatically. It counts cells and also measures the size, shape, intensity and texture of every cell (and every labeled subcellular compartment) in every image. It was designed for high throughput screening but can perform automated image analysis for images from time-lapse movies and low-throughput experiments. CellProfiler has an increasing number of algorithms to identify and measure properties of neuronal cell types.
View all literature mentionsMicroscope with differential interference contrast ,bright field, dark field components. TR30-2 Trinocular observation head with WH10X 22 eyepieces. 0.5X parfocal C mount camera adapter. Universal reflected and transmitted light stage. Capable of both transmitted and reflected light observations.
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