A5057137111- RNA modifications and cancer
- Chromatin Remodeling and Cancer
- Acute Myeloid Leukemia Research
- Radiomics and Machine Learning in Medical Imaging
- Cancer-related gene regulation
- Lung Cancer Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- NF-κB Signaling Pathways
- Cancer Mechanisms and Therapy
- Lung Cancer Treatments and Mutations
- Genetic factors in colorectal cancer
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Cancer-related molecular mechanisms research
- Lymphoma Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Cancer Cells and Metastasis
- Peptidase Inhibition and Analysis
- Research on Leishmaniasis Studies
- Molecular Biology Techniques and Applications
- Cancer-related Molecular Pathways
- Single-cell and spatial transcriptomics
- Hedgehog Signaling Pathway Studies
- Genomics and Rare Diseases
Dana-Farber Cancer Institute
2013-2025
Princess Margaret Cancer Centre
2019-2025
Harvard University Press
2024
Humber College
2024
Broad Institute
2013-2022
Harvard University
2012-2022
University Health Network
2019-2021
Cancer Institute (WIA)
2021
Massachusetts Institute of Technology
2019
McMaster University
2008-2016
TP53, which encodes the tumor suppressor p53, is most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic leukemia cell lines of common TP53 mutations. Functional, DNA-binding, transcriptional analyses revealed loss function but no GOF effects. Comprehensive scanning p53 single-amino acid...
Abstract Radiotherapy is one of the mainstays anticancer treatment, but relationship between radiosensitivity cancer cells and their genomic characteristics still not well defined. Here, we report development a high-throughput platform for measuring radiation survival in vitro its validation comparison with conventional clonogenic analysis. We combined results from this assay parameters cell lines squamous lung carcinoma, which standardly treated by radiotherapy, to identify that predict...
Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation distinct protein products with diverse functions. In genome-scale screen for inducers epithelial-to-mesenchymal transition (EMT), we found striking enrichment RNA-binding proteins. We validated that QKI RBFOX1 were necessary sufficient to induce an intermediate mesenchymal cell state increased tumorigenicity. Using RNA-seq eCLIP analysis, coordinately regulated function...
Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as therapeutic target several cancers because it many reported with role cancer progression, including FOXO4, MDM2, N-Myc, PTEN. The multi-substrate nature of USP7, combined the modest potency selectivity early generation inhibitors, presented challenge defining predictors...
Background Recent evidence suggests that human breast cancer is sustained by a minor subpopulation of tumor-initiating cells (BTIC), which confer resistance to anticancer therapies and consequently must be eradicated achieve durable cure. Methods/Findings To identify signaling pathways might targeted eliminate BTIC, while sparing their normal stem progenitor cell counterparts, we performed global gene expression profiling BTIC- mammary epithelial stem/progenitor cell- enriched cultures...
3q26 is frequently amplified in several cancer types with a common region containing 20 genes. To identify driver genes this region, we interrogated the function of each these by loss- and gain-of-function genetic screens. Specifically, found that TLOC1 (SEC62) was selectively required for proliferation cell lines amplification. Increased expression induced anchorage-independent growth, second gene, SKIL (SNON), facilitated invasion immortalized human mammary epithelial cells. Expression...
Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide in an open reading frame (ORF) expression screen and tumor xenografts. overexpression is essential enzalutamide-resistant patient-derived organoid. In AR-expressing cancer cells, interactions enhance AR activity at a subset...
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries identify potential drug targets specific for these cancers. We discovered MDM2 MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) ATSP-7041 (MDM2/4-dual),...
Abstract PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations amplification of are found across cancer types. GSK2830371 is potent selective allosteric inhibitor PPM1D, but its mechanism binding inhibition catalytic activity unknown. Here we use computational, biochemical functional genetic studies to elucidate molecular basis activity. These data confirm binds an site with high affinity. By further...
Microsatellite instability-high (MSI-H) tumors are malignant that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H is frameshift mutation RPL22, ribosomal protein. Here, we identified RPL22 as modulator MDM4 splicing through an alternative switch exon 6. loss increases 6 inclusion and cell proliferation augments resistance to MDM inhibitor Nutlin-3a. represses expression its paralog, RPL22L1, by mediating cryptic corresponding...
Metastasis is a complex and poorly understood process. In pancreatic cancer, loss of the transforming growth factor (TGF)-β/BMP effector SMAD4 correlated with changes in altered histopathological transitions, metastatic disease, poor prognosis. this study, we use isogenic cancer cell lines to identify regulated genes that contribute development colonization. We perform an vivo screen identifying FOSL1 as both target sufficient drive colonization lung. The targeting these early treatment may...
Chromatin remodeling complexes, such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, play key roles in regulating gene expression by modulating nucleosome positioning. The core subunit SMARCB1 is essential for these functions, it anchors complex to acidic patch, enabling effective chromatin remodeling. While biallelic inactivation of a hallmark several aggressive pediatric malignancies, functional implication missense mutations not fully understood. Current diagnostic approaches...
SMARCB1-deficient cancers are aggressive and highly lethal pediatric malignancies. Loss of SMARCB1 protein expression, a subunit within the SWI/SNF chromatin remodeling complex, remains key diagnostic feature these cancers. This can occur through large deletions, balanced translocations, frameshift mutations, or truncating nonsense mutations. Here, we sought to understand effect missense mutations on tumor suppressor function deep mutational scanning (DMS). Specifically, developed introduced...
Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, human counterpart of which lacks effective therapeutic options. Depletion p53-deficient cells impaired tumor initiation and maintenance vitro vivo Mechanistic studies reveal that translation-associated pathways were enriched for downstream targets, implicating translation control. In particular, loss led to decrease methylation complex,...
// Robin M. Hallett 1 , Adele Girgis-Gabardo William D. Gwynne Andrew O. Giacomelli Jennifer N.P. Bisson Jeremy E. Jensen Anna Dvorkin-Gheva 2 John A. Hassell 1, 2, 3 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada Pathology Molecular Medicine, Biology, ON, Correspondence to: Hassell, email: hassell@mcmaster.ca Keywords: breast cancer, tumor-initiating cells, serotonin antagonists, anticancer stem cell drugs Received: April 01,...
Abstract Purpose: Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit vitro and vivo efficacy against preclinical models rhabdoid tumor. Experimental Design: screened eight tumor cell lines with 481 compared their sensitivity 879 other cancer lines. Genome-scale CRISPR–Cas9 inactivation screens were analyzed confirm target vulnerabilities. Gene expression data queried across primary discover biomarkers...
Abstract Genome sequencing studies have identified millions of somatic variants in cancer, but their phenotypic impact remains challenging to predict. Current experimental approaches distinguish between functionally impactful and neutral require customized assays that often report on average effects, are not easily scaled. Here, we develop a generalizable, high-dimensional, scalable approach assess variant single cells by pooled Perturb-seq. Specifically, assessed the 200 TP53 KRAS...
Summary Microsatellite instability high (MSI-H) tumors are malignant that, despite harboring a mutational burden, often have intact TP53 . One of the most frequent mutations in MSI-H is frameshift mutation RPL22 , ribosomal protein. Here, we identified as modulator MDM4 splicing through an alternative switch exon 6. loss increases 6 inclusion, cell proliferation, and augments resistance to MDM inhibitor Nutlin-3a. represses expression its paralog, RPL22L1, by mediating cryptic corresponding...
Abstract To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and G12D mutant alleles. We defined spectrum of oncogenic potential nearly all possible variants, identifying several novel transforming alleles elucidating a model to describe frequency mutations human cancer as function potential, probability, tissue-specific signatures. Biochemical structural analyses variants identified second-site suppressor...