A5061265510- Glioma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Neuroblastoma Research and Treatments
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- ATP Synthase and ATPases Research
- Ferroptosis and cancer prognosis
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- Genomics and Chromatin Dynamics
- Cancer-related molecular mechanisms research
- DNA Repair Mechanisms
- Sarcoma Diagnosis and Treatment
- Cancer-related gene regulation
- Cancer, Hypoxia, and Metabolism
- melanin and skin pigmentation
- Immunotherapy and Immune Responses
- Protein Degradation and Inhibitors
- Molecular Biology Techniques and Applications
- Renal and related cancers
- RNA Research and Splicing
- Lymphoma Diagnosis and Treatment
- interferon and immune responses
- Lung Cancer Treatments and Mutations
- Histone Deacetylase Inhibitors Research
Hospital for Sick Children
2016-2025
SickKids Foundation
2015-2024
Great Ormond Street Hospital
2023
University College London
2023
Brain Tumour Research
2015-2021
University of Toronto
2019-2021
University of Oxford
2011-2020
Ludwig Cancer Research
2015-2020
Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors a higher mortality rate, while high-grade better outcome. However, we little understanding of their biology therefore cannot explain this nor what constitutes optimal management. Here report comprehensive genetic analysis an international cohort clinically annotated infant gliomas, revealing 3 subgroups. Group 1 arise the cerebral hemispheres harbor alterations receptor tyrosine...
The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, drug However, how MITF suppressed in vivo...
Abstract Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify reciprocal antagonism between melanocyte lineage transcription factor MITF c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness melanoma cells favouring myeloid cell recruitment. We show that cytokines such as TNF-α instigate...
Microphthalmia-associated transcription factor (MITF) is the master regulator of melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive interactome identifying novel cofactors involved in DNA replication repair, chromatin organisation. We show that interacts with PBAF remodelling complex comprising BRG1 CHD7. essential for melanoma cell proliferation vitro normal development vivo. SOX10 actively...
Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due their sensitive midline location. As such, genetic analysis for biomarkers aid diagnosis, prognosis treatment of these is needed. Here, we identified 64 thalamic gliomas with clinical follow-up characterized targeted genomic alterations using newly optimized droplet digital NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63–17.55) survival...
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms action ACVR1 unknown. Using mouse models, we demonstrate that Acvr1
Although replication repair deficiency, either by mismatch deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark MMRD alone. By genome-wide analysis tumors with germline and somatic deficiencies repair, we reveal novel association between proofreading MSI, especially when both components are lost. Analysis indels microsatellites (MS-indels) identified five distinct signatures (MS-sigs)....
Abstract Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These promote oncogenesis by dysregulating gene expression through alterations of modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability H3.3 mutant pHGG, opens new therapeutic options. The two most frequent K27M G34R, drive replication-associated damage non-homologous end joining (NHEJ). Aberrant NHEJ is...
The v-ATPase is a fundamental eukaryotic enzyme central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 well-documented, our knowledge of mechanisms that regulate activity limited. Here, we report the Drosophila transcription factor Mitf master regulator this holoenzyme. directly controls all 15 components through M-box cis-sites and coordinated regulation impacts holoenzyme in vivo. In addition, v-ATPase, promotes TORC1, which turn negatively regulates...
Abstract Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor nongenomic drivers. We therefore investigated role alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured a cohort 60 The implication mtDNA alteration pHGG tumorigenesis studied followed by efficacy investigation using...
Abstract Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified haematopoietic malignancies and carcinomas. H3K27M functions, at least part, through widespread changes H3K27 trimethylation its role tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M diverse progenitor cell populations. expression drives tumorigenesis multiple tissues, which is further enhanced...
It is widely assumed that decreasing transcription factor DNA-binding affinity reduces initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo factors find their binding sites while confronted with a large excess low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as model, we show act competitive reservoir from which are released mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased...
Abstract With the success of immunotherapy in cancer, understanding tumor immune microenvironment (TIME) has become increasingly important; however pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile diverse range 1382 samples with detailed molecular annotation. In low-grade gliomas identify distinct patterns activation prognostic significance BRAF V600E-mutant tumors. high-grade gliomas,...
Poly adenosine diphosphate (ADP)–ribosylation (PARylation) by poly ADP-ribose (PAR) polymerases (PARPs) is an early response to DNA double-strand breaks (DSBs). In this paper, we exploit Dictyostelium discoideum uncover a novel role for PARylation in regulating nonhomologous end joining (NHEJ). occurred at single-strand breaks, and two PARPs, Adprt1b Adprt2, were required resistance kind of damage. contrast, although was dispensable DSBs, Adprt1a and, lesser extent, Adprt2 event. Disruption...
Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models pHGA DIPG. levels were characterized DIPG patient samples tumor-derived cell lines. The effects PARP inhibitors veliparib, olaparib, niraparib as monotherapy or radiosensitizers on viability, DNA damage, activity evaluated a panel Survival benefit was...
Abstract In response to the dynamic intra‐tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of microphthalmia‐associated transcription factor (MITF). The hypoxia is driven by hypoxia‐inducible factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF can activate expression. Although HIF share a highly related DNA‐binding specificity, it unclear whether they co‐regulate subset target genes....
The RAS/MAPK pathway is an emerging targeted across a spectrum of both adult and pediatric cancers. Typically, this associated with single, well-characterized point mutation in oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation such targetable genomic events. We find replication repair-deficient (RRD) cancers, which are universally hypermutant affect children born RRD cancer predisposition, enriched for (P = 10-8). These not random, exist...
Abstract High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While genetic drivers HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate alternative splicing landscape pediatric and adult through multi-omic analyses, uncovering an increased burden compared with normal brain. The rate recurrent in cancer exceeds their mutation rate, a pattern that recapitulated pan-cancer...
Abstract Background Diffuse Midline Glioma (DMG) is a highly aggressive pediatric brain tumor with limited treatment options despite extensive genomic characterization. The aim of this study was to investigate the proteomic landscape DMG identify potential therapeutic targets. Methods We conducted comprehensive analysis using LC-MS3, along DNA methylation and DNA/RNA sequencing in 55 patients’ samples. PTM profiling (phosphoproteome methylproteome) 30 patient then investigated effects...
Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation protein ID1 H3K27M ACVR1 mutations in DMG, but this has not been confirmed human or therapeutically targeted.
Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M lead to global disruption H3K27me3 through dominant negative PRC2 inhibition, while H3G34R local losses H3K36me3 inhibition SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M H3.3G34R interactomes, finding that is associated with epigenetic transcription factor changes; in contrast removes a break on...
Chromatin structure, transcription, DNA replication, and repair are regulated via locus-specific incorporation of histone variants posttranslational modifications that guide effector chromatin-binding proteins. Here we report unbiased, quantitative interactomes for the replication-coupled (H3.1) replication-independent (H3.3) H3 based on BioID proximity labeling, which allows interactions in intact, living cells to be detected. Along with a significant proportion previously reported detected...