A5021305853- Melanoma and MAPK Pathways
- Advanced Breast Cancer Therapies
- Protein Degradation and Inhibitors
- Cancer Cells and Metastasis
- Cellular Mechanics and Interactions
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Synthesis of Tetrazole Derivatives
- CAR-T cell therapy research
- Protein Kinase Regulation and GTPase Signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Mechanisms of cancer metastasis
- Immune Response and Inflammation
- Cancer-related Molecular Pathways
- Cancer Mechanisms and Therapy
- Hippo pathway signaling and YAP/TAZ
- HER2/EGFR in Cancer Research
- Nitric Oxide and Endothelin Effects
- Click Chemistry and Applications
- Synthesis and biological activity
- Electrospun Nanofibers in Biomedical Applications
- Synthesis and Characterization of Heterocyclic Compounds
- Chemical synthesis and alkaloids
- Boron Compounds in Chemistry
- Silk-based biomaterials and applications
Harrison Medical Center
2024
Institute of Cancer Research
2011-2023
Cancer Research UK
2011-2020
Institute of Cancer Research
2016
Centre for Cancer Biology
2014
Inserm
2009-2012
Aix-Marseille Université
2007-2012
Institut Pasteur de Tunis
2007
Mécanismes de Tumorigenèse et Thérapies Ciblées
2007
Centre National de la Recherche Scientifique
2007
Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation cancer initiation or progression is not known. Here, we provide evidence ROCK1 ROCK2 act redundantly to maintain actomyosin contractility cell loss leads cell-cycle arrest cellular senescence. This phenotype arises from down-regulation essential proteins CyclinA, CKS1 CDK1. Accordingly, while either Rock1 Rock2 had no negative impact on...
Abstract There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit Rho-kinases ROCK 1 2 we show they potently activity in melanoma cells culture vivo. Treatment with CCT129254 or dramatically reduces cell invasion, impairing both “amoeboid-like” mesenchymal-like modes invasion culture. Intravital...
Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling changes expression activity ROCK-myosin II pathway during acquisition to MAPK inhibitors. regulates myosin activity, but after initial therapy response, drug-resistant clones restore increase survival. High correlates with aggressiveness, identifying therapy- immunotherapy-resistant melanomas. Survival resistant cells is...
Melanoma cells can switch between an elongated mesenchymal-type and a rounded amoeboid-type migration mode. The 'amoeboid' form of cell movement is driven by actomyosin contractility resulting in membrane blebbing. Unlike A375 melanoma cells, do not display any obvious morphological front-back polarisation, although polarisation thought to be prerequisite for movement. We show that blebbing are polarised, with ezrin (a linker the plasma actin cytoskeleton), F-actin, myosin light chain,...
Polarization of cells into a protrusive front and retracting cell body is the hallmark mesenchymal-like migration. Many mRNAs are localized to protrusions, but it unclear what degree mRNA localization contributes toward protrusion formation. We performed global quantitative analysis distributions mRNAs, proteins, translation rates between protrusions by RNA sequencing (RNA-seq) proteomics. Our results reveal local as key determinant protein protrusions. Accordingly, inhibition destabilizes...
Background and purpose: Oxaliplatin is the first platinum‐based compound effective in treatment of colorectal cancer. combined with cetuximab for metastatic cancer under evaluation. The preliminary results seem controversial, particularly use K‐Ras mutated patients. mutation known to affect redox homeostasis. Here we evaluated how efficacy oxaliplatin alone or varied according Ras status a panel tumour cell lines. Experimental approach: Viability was by methylthiazoletetrazolium assay,...
Escherichia coli is the most extensively used host for production of recombinant proteins. However, eukaryotic proteins are typically obtained as insoluble, misfolded inclusion bodies that need solubilization and refolding. To achieve high-level expression soluble human interferon alpha (rhIFNalpha) in E. coli, we have first constructed a plasmid (pGEX-hIFNalpha2b), which merged hIFNalpha2b cDNA with glutathione S-transferase (GST) coding sequence downstream tac-inducible promoter. Using...
Abstract The catalytic subunit of the NADPH oxidase complex, Nox1 (homologue gp91phox/Nox2), expressed mainly in intestinal epithelial and vascular smooth muscle cells, functions innate immune defense cell proliferation. molecular mechanisms underlying these functions, however, are not completely understood. We measured Nox1‐dependent O production during spreading on Collagen IV (Coll IV) colon carcinoma lines. Knocking down by shRNA, we showed that is activated after 4 hr adhesion IV....
Abstract The CRL4 CRBN ubiquitin ligase is leveraged by molecular glue degraders, small molecules that reprogram specificity to induce degradation of clinically relevant neosubstrate proteins. Known neosubstrates share a generalizable β-hairpin G-loop recognition motif, yet systematic exploration the target landscape still pending. Through computational mining human proteome using structure-based approaches, we predict over 1,400 CRBN-compatible proteins across diverse classes, identify...
Molecular glue degraders (MGDs) are small molecule compounds that repurpose the ubiquitin-proteasome system to induce degradation of challenging therapeutic targets. Thalidomide-analogs clinically effective MGDs bind cereblon (CRBN), a substrate receptor Cullin-4/RING E3 ubiquitin ligase (CRL4CRBN), and impose gain-of-function activity recruit, ubiquitinate degrade so-called neosubstrate proteins. Known neosubstrates CRBN/MGD neosurface on CRBN CULT domain through structural G-loop...
Melanoma cells can adopt two functionally distinct forms, amoeboid and mesenchymal, which facilitates their ability to invade colonize diverse environments during the metastatic process. Using quantitative imaging of single living tumor invading three-dimensional collagen matrices, in tandem with unsupervised computational analysis, we found that melanoma switch between mesenchymal forms via different routes shape space--an apolar polar route. We show whereas particular Rho-family GTPases...
Abstract Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and rapidly translating into clinical agents. However, fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed issue in design CRL4 CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used generate PROTACs have well described intrinsic monovalent profiles by recruitment neo‐substrates,...
NADPH oxidase 1 (Nox1) is expressed mainly in colon epithelial cells and produces superoxide ions as a primary function. We showed that Nox1 knockdown inhibits directional persistence of migration on collagen I. This paper dissects the mechanism by which affects direction colonic cell two-dimensional model. Transient activation during spreading temporarily inactivated RhoA led to efficient exportation alpha2beta1 integrin surface, supported persistent directed migration. loss takes place...
Cellular behavior is strongly influenced by the architecture and pattern of its interfacing extracellular matrix (ECM). For an artificial culture system which could eventually benefit translation scientific findings into therapeutic development, should capture key characteristics a physiological microenvironment. At same time, it also enable standardized, high throughput data acquisition. Since ECM composed different fibrous proteins, studying cellular interaction with individual fibrils...
To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag on IMiDs/CELMoDs mechanism of action that improves and addresses limitations both PROTAC previous IMiDs/CeLMoDs tags. Using structural sequence analysis, systematically explored native chimeric containing domains (DCDs) evaluated their ability to induce degradation. We identified optimal iTAG(DCD23 60aa) elicits robust degradation targets across cell types subcellular localizations without...
Endothelial filopodia play key roles in guiding the tubular sprouting during angiogenesis. However, their dynamic morphological characteristics, with associated implications cell motility, have been subjected to limited investigations. In this work, interaction between endothelial cells and extracellular matrix fibrils was recapitulated vitro, where a specific focus paid derive parameters define dynamics of filopodium-like protrusion motility. Based on one-dimensional gelatin patterned by...
Abstract The Myc family of transcription factors is a well-established driver human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy directly targeting members has been developed to date. Abnormal activation results in uncontrolled cell growth that associated with high translational output ramp up protein machinery. This creates dependency translation turn represents potential therapeutic vulnerability for Myc-driven...
<p>Supplementary Figure S4. Images of lung parenchyma invaded by both orange (CCT54-treated) cells and green (vehicle -treated) cells.</p>