A5090314471- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- PI3K/AKT/mTOR signaling in cancer
- Protein Tyrosine Phosphatases
- Genomic variations and chromosomal abnormalities
- RNA modifications and cancer
- Hippo pathway signaling and YAP/TAZ
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Protease and Inhibitor Mechanisms
- Calpain Protease Function and Regulation
- Cellular transport and secretion
- Synthesis and biological activity
- Developmental Biology and Gene Regulation
- Cancer therapeutics and mechanisms
- Cancer-related gene regulation
- RNA regulation and disease
- Gene expression and cancer classification
- Cell death mechanisms and regulation
- Animal Genetics and Reproduction
Novartis (Switzerland)
2023-2024
Novartis Institutes for BioMedical Research
2023
The Francis Crick Institute
2016-2018
CRUK Lung Cancer Centre of Excellence
2017
University College London
2017
The Honourable Society of Lincoln's Inn
2016
Cancer Research UK
2011-2014
McGill University
2004-2010
McGill University Health Centre
2008
Molecular Oncology (United States)
2006-2007
The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution small insertions and deletions (indels) less well characterised. We investigated whether frameshift nature indel mutations, which create novel open reading frames a large quantity mutagenic peptides highly distinct from self, might contribute to immunogenic phenotype.
The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all...
Abstract Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, pharmacologic approaches identify CIN-survival factors diploid cells. We find partial...
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis colorectal cancers cell lines, we find frequent loss heterozygosity mutations in BCL9L tumors. deficiency promoted missegregation events, aneuploidy, genetic heterogeneity xenograft models likely through modulation Wnt signaling. We...
It is generally accepted that the role of cathepsin L in cancer involves its activities outside cells once it has been secreted. However, isoforms are devoid a signal peptide were recently shown to be present nucleus where they proteolytically process CCAAT-displacement protein/cut homeobox (CDP/Cux) transcription factor. A for nuclear cell proliferation could inferred from observation CDP/Cux processed isoform can accelerate entry into S phase. Here, we report many transformed proteolytic...
Abstract Mutations in PIK3CA are very frequent cancer and lead to sustained PI3K pathway activation. The impact of acute expression mutant during early stages malignancy is unknown. Using a mouse model activate the Pik3ca H1047R hotspot mutation heterozygous state from its endogenous locus, we here report that induces centrosome amplification cultured cells (through involving AKT, ROCK CDK2/Cyclin E-nucleophosmin) tissues, increased vitro cellular tolerance spontaneous genome doubling. We...
Abstract The YAP-TEAD protein-protein interaction (PPI) is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Current advanced pharmacological agents which aim at inhibiting function do so by engaging into lipid pocket TEAD. Thereby consequences direct disruption interface and TEADs remain unexplored. Here we report identification IAG933, first molecule able potently directly disrupt YAP/TAZ-TEADs PPI with suitable properties enter in clinical trial....
The CDP/Cux transcription factor was previously found to acquire distinct DNA binding and transcriptional properties following a proteolytic processing event that takes place at the G1/S transition of cell cycle. In present study, we have investigated role processed isoform, p110, in cycle progression. Populations cells stably expressing p110 displayed faster division rate reached higher saturation density than control carrying empty vector. next S phase under various experimental...
Abstract Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non–small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The inhibitor JDQ443 shows enhanced preclinical antitumor combined the SHP2 TNO155, combination currently under evaluation. To identify rational strategies that could help overcome or prevent some types resistance, we evaluated duration responses to ± alone PI3Kα...
In this study, we investigated the mechanism by which CUX1 transcription factor can stimulate cell migration and invasion. The full-length p200 had a weaker effect than proteolytically processed p110 isoform; moreover, treatments that affect processing similarly impacted migration. We conclude stimulatory of is mediated in part, if not entirely, through generation CUX1. established list putative transcriptional targets with functions related to motility, then identified those whose...
Proteolytic processing of the CUX1 transcription factor generates an isoform, p110 that accelerates entry into S phase. To identify targets are involved in cell cycle progression, we performed genome-wide location analysis using a promoter microarray. Since there no antibodies specifically recognize p110, but not full-length protein, expressed physiological levels isoform with two tags and purified chromatin by tandem affinity purification (ChAP). Conventional ChIP on synchronized...
Cell populations able to generate a large repertoire of genetic variants have increased potential tumor cells that survive through the multiple selection steps involved in progression. A mechanism for generation aneuploid cancer involves passage tetraploid stage. Supernumerary centrosomes, however, can lead multipolar mitosis and cell death. Using tissue culture transgenic mouse models breast cancer, we report Cut homeobox 1 (CUX1) causes chromosomal instability by activating transcriptional...
The p110 CUX1 homeodomain protein participates in the activation of DNA replication genes part by increasing affinity E2F factors for promoters these genes. expression is very weak quiescent cells and increases during G(1). Biochemical activities associated with transcriptional are potentiated post-translational modifications late G(1), notably a proteolytic processing event that generates CUX1. Constitutive CUX1, as observed some transformed cells, leads to accelerated entry into S phase....
<p>Supplementary Figure S1: Using reversine to cause chromosome segregation errors and p53-dependent aneuploidy tolerance. Supplementary S2: Validation of APC/C subunits using siRNA deconvolution experiments in RPE1 HCT116 cells, how subunit knock-down rescues proliferation when the spindle assembly checkpoint is impaired. S3: reduces caused by SAC defects. S4: CRISPR-mediated disruption TP53 CDC27, resistance Mps1 inhibitors. S5: Functional testing CDC27 mutations Schizosaccharomyces...