A5091762406- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Chronic Myeloid Leukemia Treatments
- Peroxisome Proliferator-Activated Receptors
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- RNA modifications and cancer
- DNA Repair Mechanisms
- Chronic Lymphocytic Leukemia Research
- Click Chemistry and Applications
- MicroRNA in disease regulation
- Cancer, Lipids, and Metabolism
- Eosinophilic Disorders and Syndromes
- Multiple Myeloma Research and Treatments
- CRISPR and Genetic Engineering
- Signaling Pathways in Disease
- RNA Interference and Gene Delivery
- Pluripotent Stem Cells Research
- Cell death mechanisms and regulation
- Peptidase Inhibition and Analysis
- Circular RNAs in diseases
- Cell Image Analysis Techniques
- Cancer Mechanisms and Therapy
- Microtubule and mitosis dynamics
- interferon and immune responses
The University of Texas at Austin
2004-2025
University of Minnesota
2025
Boston Children's Hospital
2007-2021
Harvard University
2007-2021
Dana-Farber Cancer Institute
2010-2021
Boston Children's Museum
2015-2017
Harvard Stem Cell Institute
2009-2016
Howard Hughes Medical Institute
2010-2014
University of Massachusetts Boston
2010
Brigham and Women's Hospital
2009
Neuroblastoma (NB) is a highly metastatic pediatric cancer arising from the neural crest lineage. Genetic amplification of MYCN proto-oncogene defining feature NB, present in about 20% all cases. The let-7 tumor suppressor microRNA targets 3-prime UTR mRNA. We previously demonstrated that mRNA acquires ability to sequester MYCN-amplified (MA) disease, thus inhibiting its function. This work established noncoding element within an oncogenic can contribute independently disease pathology and...
Abstract The p53 tumor suppressor protein is phosphorylated and activated by several DNA damage-inducible kinases, such as ATM, a key effector of the damage response promoting cell cycle arrest or apoptosis. Deregulation Rb-E2F1 pathway also results in activation promotion apoptosis, this contributes to suppression development. Here, we describe novel connection between E2F1 ATM pathway. In primary human fibroblasts lacking functional ability induce phosphorylation apoptosis impaired....
Overexpression of the c-myc oncogene contributes to development a significant number human cancers. In response deregulated Myc activity, p53 tumor suppressor is activated promote apoptosis and inhibit formation. Here we demonstrate that induction in overexpression requires ataxia-telangiectasia mutated (ATM) kinase, major regulator cellular DNA double-strand breaks. transgenic mouse model overexpressing squamous epithelial tissues, inactivation Atm suppresses accelerates tumorigenesis....
Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) entails a mesenchymal epithelial transition (MET).While attempting dissect the mechanism MET during reprogramming, we observed that knockdown (KD) epithelial-to-mesenchymal (EMT) factor SNAI1 (SNAIL) paradoxically reduced, while overexpression enhanced, reprogramming efficiency in human and mouse cells, depending on strain.We nuclear localization at an early stage fibroblast using expressing knockin SNAI1-YFP reporter...
The Zcchc11 enzyme is implicated in microRNA (miRNA) regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA embryonic stem cell lines, suggested mediate maintenance. miR-26 relieve silencing activity without impacting content cancer cytokine and growth factor expression. Broader roles shaping or remodeling miRNome directing biological physiological processes remain entirely speculative. We generated Zcchc11-deficient mice address these knowledge gaps....
Significance LIN28B is well known as a RNA-binding protein and suppressor of microRNA biogenesis by selectively blocking the processing let-7 precursors. However, little about –independent roles LIN28B. Here, we show that recruited to active promoters binding zinc-finger transcription factor ZNF143. acts cofactor upregulate expression subset downstream target genes are essential for neuroblastoma cell survival migration. Our paper reveals an unexpected role in transcriptional regulation...
Background/Objectives: Neuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood deaths despite only having ~8% incidence. The current standard care high-risk diseases genotoxic. This, combined with less than 50% survival in and an abysmal 5% relapsed cases, makes discovering novel, effective, toxic treatments essential. Methods: A prophylactic syngeneic mouse model was used to test high-dose lipid-mediator unsaturated fatty acids on...
Mice and primary fibroblasts derived from mouse embryos completely lacking cytoplasmic β-actin, because the Actb gene was engineered to instead express γ-actin protein, have previously been found be virtually devoid of phenotype. Here, we report characterization mice embryonic homozygous for an Actg1 allele edited translate β-actin (Actg1-coding beta; Actg1c-b/c-b), which resulted in that are γ-actin. We demonstrate these Actg1c-b/c-b present with no measurable phenotype survival, body mass,...
Abstract Neuroblastoma (NB) is a highly metastatic pediatric cancer originating from neural crest cells. Progression frequently driven by MYCN amplified (MA) disease, marker of poor prognosis presented in approximately 20% cases. While MA NB associated with increased protein expression, recent results suggest that non-coding RNA (ncRNA) elements within the mRNA independently contribute to its oncogenic potential. The let-7 microRNA (miRNA) family, which targets 3′ UTR MYCN, sequestered...
The ARF tumor suppressor participates in a p53-dependent apoptotic pathway that is stimulated response to some oncogenic stimuli. E2F1 transcription factor critical downstream target of the Rb and, when active, can promote proliferation as well apoptosis. finding transcriptionally regulates gene has led suggestion contributes E2F1-induced Counter this hypothesis, study demonstrates not only unnecessary for induce apoptosis but also inactivation actually enhances ability Inactivation...
High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that was enhanced cell migration in vitro invasive metastatic behavior murine xenografts. Sequence analysis the polyribosome fraction LIN28B-expressing cells revealed let-7–independent enrichment transcripts encoding components translational ribosomal apparatus depletion neuronal developmental programs. We further observed utilizes both...
AbstractActivation of the ATM DNA damage response pathway is commonly observed in avariety early-stage neoplasias. It has been proposed that this checkpoint responsefunctions to suppress development cancer. A recent report from our laboratorydemonstrates does indeed function tumorigenesis byresponding at least some oncogenic stresses. Transgenic expression Myc isfound cause vivo and shown respond byinducing accumulation phosphorylation p53. In absence ATM, p53-dependent apoptosis reduced...
MYCN amplification (MNA) and disruption of tumor suppressor microRNA (TSmiR) function are key drivers poor outcomes in neuroblastoma (NB). While TSmiRs regulate glucose metabolism, their role de novo fatty acid synthesis (FAS) unsaturated FAS (UFAS) remains poorly understood. Here, we show that UFAS (U/FAS) genes FASN, ELOVL6, SCD, FADS2, FADS1 upregulated high-risk (HR) NB expression is associated with lower overall survival. RNA-Seq analysis human cell lines revealed parallel U/FAS gene...
Mutation in the ABL kinase domain is principal mechanism of imatinib resistance patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most variants, but are ineffective against gatekeeper mutant, T315I. Gatekeeper mutation activates by stabilizing hydrophobic spine. Here, we describe that rationally designed compound AP24163 can native mutants kinase. Structural modelling suggests affects flexibility P-loop...
It is unknown which post-transcriptional regulatory mechanisms are required for oncogenic competence. Here, we show that the LIN28 family of RNA-binding proteins (RBPs), facilitate RNA metabolism within ribonucleoprotein networks, essential initiation diverse oncotypes hepatocellular carcinoma (HCC). In HCC models driven by NRASG12V/Tp53, CTNNB1/YAP/Tp53, or AKT/Tp53, mice without Lin28a and Lin28b were markedly impaired in cancer initiation. We biochemically defined an oncofetal regulon 15...
Abstract Precision in genetic modeling of oncogene-driven cancer is crucial for comprehending disease pathology. Traditionally, models focused on protein expression through open-reading-frame (ORF) transgenes. This approach overlooks post-transcriptional regulation endogenous mRNAs, which include noncoding elements like 5’ and 3’ UTRs introns. All patient oncogene mRNAs encompass these elements, grasping the collective impact coding components may revolutionize our comprehension...
Abstract Neuroblastoma (NB) is a devastating neural crest-derived tumor primarily affects children under five. Forty percent of NB patients are classified as high-risk (HR), and less than half them survive. HR disease split into two equally sized groups: one exhibiting genetic amplification the MYCN proto-oncogene (MA), another where non-amplified (MNon). Overall survival (OS) studies often either poorly annotated or focused on outcomes across entire patient group, which may mask...
Abstract Dysregulated metabolism is a hallmark of cancer. While the role glucose in cancer has been extensively studied, relatively little done to understand poly-unsaturated fatty acids biology. To gain insight into their contribution progression we determined expression patterns and outcome associations both saturated unsaturated acid synthesis (UFAS) genes pediatric neuroblastoma (NB), levels NB cell lines derived from high-risk tumors. MYCN amplification disruption tumor suppressor...