A5010955572- Chromatin Remodeling and Cancer
- Ferroptosis and cancer prognosis
- Advanced Breast Cancer Therapies
- Epigenetics and DNA Methylation
- Lung Cancer Research Studies
- Radiomics and Machine Learning in Medical Imaging
- Cancer Mechanisms and Therapy
- Neuroendocrine Tumor Research Advances
- Mechanisms of cancer metastasis
- DNA Repair Mechanisms
- Metabolism, Diabetes, and Cancer
- MicroRNA in disease regulation
- Chronic Lymphocytic Leukemia Research
- Lung Cancer Treatments and Mutations
- Cancer Risks and Factors
- Gestational Trophoblastic Disease Studies
- RNA modifications and cancer
- Microtubule and mitosis dynamics
- Phagocytosis and Immune Regulation
- Acute Myeloid Leukemia Research
- Nuclear Receptors and Signaling
- BRCA gene mutations in cancer
- PARP inhibition in cancer therapy
- Cancer Immunotherapy and Biomarkers
- Cancer-related molecular mechanisms research
University Health Network
2024
Princess Margaret Cancer Centre
2024
McGill University
2019-2024
Lunenfeld-Tanenbaum Research Institute
2021-2023
McGill University Health Centre
2015-2021
Mount Sinai Hospital
2021
Peking Union Medical College Hospital
2014
Chinese Academy of Medical Sciences & Peking Union Medical College
2014
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and not directly druggable. We recently uncovered that loss an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility CDK4/6 inhibition. Here, we show this vulnerability conserved non-small cell lung (NSCLC), where also results reduced expression selective sensitivity inhibitors. In addition, SMARCA2, another subunit lost subset of NSCLCs, regulates drug...
Abstract The PD-L1 (CD274) immune-checkpoint ligand is often upregulated in cancers to inhibit T cells and elicit immunosuppression. Independent of this activity, has recently been shown also exert a cancer cell–intrinsic function promoting tumorigenesis. Here, we establish tumor-intrinsic role triple-negative breast (TNBC) non–small cell lung (NSCLC). Using FACS-assisted shRNA screens, identified the cell-surface adhesion receptor CD44 as key positive regulator expression these cancers....
Abstract Inactivating mutations in SMARCA4 ( BRG1 ), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to inhibition cyclin-dependent kinase 4/6 (CDK4/6). loss causes profound downregulation cyclin D1, which limits CDK4/6 activity leads vitro vivo susceptibility inhibitors. patient...
Abstract Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non–small cell lung (NSCLC). However, the clinical efficacy of CDK4/6 is limited due to frequent drug resistance their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred inhibitor palbociclib in NSCLC cells. Inhibition BRD4, either by...
Abstract Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets ovarian lung cancers. Concomitant loss these key subunits SWI/SNF chromatin remodeling complexes both cancers is associated with chemotherapy resistance poor prognosis. Here, we discover that SMARCA4/2 inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca 2+ ) release By restricting accessibility to ITPR3 , encoding Ca channel IP3R3,...
Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using combination metabolomics, transcriptomics, functional genomics, we show that two anthracyclines, doxorubicin epirubicin, distinct primary vulnerabilities human breast cells. Doxorubicin-resistant cells rely on glutamine drive...
CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought better understand the resistant mechanisms help devise potential strategies overcome this challenge. We show that treatment with in both ER+ NSCLC cells induces feedback upregulation of cyclin D1, CDK4, E1, mediating...
Recurrent inactivating mutations in components of SWI/SNF chromatin-remodeling complexes have been identified across cancer types, supporting their roles as tumor suppressors modulating oncogenic signaling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET ALK inhibitors non-small cell lung cancers (NSCLCs). found binds regulatory regions the locus suppresses transcription part through regulating Polycomb Repressive Complex component CBX2....
The aim of this study was to investigate whether 6 candidate serum miRNAs and their interactions with folate level were associated the risk for pancreatic cancer (PC).A hospital-based case-control including 74 incident PC cases controls conducted. Serum determined by radioimmunoassay real-time quantitative polymerase chain reaction, respectively. Cell lines AsPC-1 PANC-1 used in vitro study.MiR-16 elevated (P = 0.030-0.043) miR-103 reduced 0.018-0.020) after adjustment age, sex, smoking;...
Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to family and usually caused by biallelic inactivation SMARCB1, encoding key subunit SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives promoting cell cycle through activating transcription cyclin D1 while suppressing p16. However, low protein expression observed in most ATRT patient tumors. The underlying...
Functional genomic screens in two-dimensional cell culture models are limited identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 a with xenografts derived from same line, we identified MEN1 as top hit confers differential dropout effects vitro and vivo. knockout multiple solid cancer types does not impact proliferation but significantly promotes or inhibits growth immunodeficient immunocompetent mice, respectively. Mechanistically,...
<div>Abstract<p>Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including <i>KRAS</i>-mutant non–small cell lung (NSCLC). However, the clinical efficacy of CDK4/6 is limited due to frequent drug resistance their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred inhibitor palbociclib in...
<div>Abstract<p>Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including <i>KRAS</i>-mutant non–small cell lung (NSCLC). However, the clinical efficacy of CDK4/6 is limited due to frequent drug resistance their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred inhibitor palbociclib in...
<p>List of common direct target genes BRD4 in KRAS-mutant NSCLC cells.</p>
<p>List of NSCLC cell lines with corresponding BRD4 mRNA levels and IC50 values for palbociclib.</p>
<p>List of supplementary data and Supplementary Figures 1-9.</p>
<div>Abstract<p>Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including <i>KRAS</i>-mutant non–small cell lung (NSCLC). However, the clinical efficacy of CDK4/6 is limited due to frequent drug resistance their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred inhibitor palbociclib in...
<p>List of NSCLC cell lines with corresponding BRD4 mRNA levels and IC50 values for palbociclib.</p>
<p>List of top candidates identified from the cDNA screen.</p>
<p>List of genes related to cell cycle that are suppressed by BRD4 inhibition.</p>
<p>List of top candidates identified from the cDNA screen.</p>
<p>List of BRD4 binding regions on gene loci related to cell cycle.</p>
<p>List of genes related to cell cycle that are suppressed by BRD4 inhibition.</p>