A5026892408- Hippo pathway signaling and YAP/TAZ
- Glioma Diagnosis and Treatment
- RNA Research and Splicing
- Neurobiology and Insect Physiology Research
- interferon and immune responses
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Microtubule and mitosis dynamics
- Cancer-related gene regulation
- Protein Kinase Regulation and GTPase Signaling
- RNA modifications and cancer
- 14-3-3 protein interactions
- Nuclear Structure and Function
- Cell death mechanisms and regulation
- Developmental Biology and Gene Regulation
- Renal and related cancers
- Studies on Chitinases and Chitosanases
- Chronic Myeloid Leukemia Treatments
- Immune cells in cancer
- Neurofibromatosis and Schwannoma Cases
- Chromatin Remodeling and Cancer
- Chronic Lymphocytic Leukemia Research
- Cancer-related molecular mechanisms research
- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
Emory University
2014-2024
Cancer Institute (WIA)
2024
Winship Cancer Institute
2020-2024
Piedmont Cancer Institute
2024
Salk Institute for Biological Studies
2007-2023
Brigham Young University
2013
Centre Eugène Marquis
2013
Centre Hospitalier Universitaire de Rennes
2013
Washington University in St. Louis
2000-2004
University of Nebraska Medical Center
1996-1997
Gliomas, the most common malignant tumors of nervous system, frequently harbor mutations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling pathways. To investigate genetic basis this disease, we developed a glioma model in Drosophila. We found constitutive coactivation EGFR-Ras PI3K pathways Drosophila glia glial precursors gives rise to neoplastic, invasive cells create transplantable tumor-like growths, mimicking human glioma. Our...
Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations activate receptor tyrosine kinase (RTK) Pi-3 (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK PI3K pathways in glial progenitor cells creates neoplastic tumors many features human glioblastoma. both Drosophila, stimulates Akt along other as-yet-unknown changes drive oncogenesis. We...
Abstract Purpose: Glioblastomas (GBMs), neoplasms derived from glia and neuroglial progenitor cells, are the most common lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months. GBM tumorigenicity is often driven by genetic aberrations receptor tyrosine kinases, such as amplification mutation EGFR. Experimental Design: Using Drosophila glioma model human patient–derived stem cells xenograft models, we genetically pharmacologically tested whether YAP TAZ...
Abstract Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12–15 months. One promising avenue research is development novel therapies targeting properties non-neoplastic cell-types within tumour such as associated macrophages (TAMs). TAMs are immunosuppressive promote malignancy adult HGG; however, paediatric medulloblastoma, exhibit anti-tumour properties. Much known about HGG, yet little them setting. This raises...
Abstract Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal multipotent differentiation. Growth is favored deregulated division, which enhances self-renewing population diminishes differentiation program. Mutation of a single gene Drosophila, Brain Tumor (Brat), leads to disrupted resulting dramatic proliferation neuroblasts massive larval brain overgrowth. To uncover mechanisms relevant human...
The c-<i>fes</i> proto-oncogene encodes a non-receptor tyrosine kinase (Fes) that has been implicated in cytokine receptor signal transduction and myeloid differentiation. Previous work from our laboratory shown Fes autophosphorylates via an intermolecular mechanism more commonly associated with growth factor kinases. Analysis of the amino acid sequence COILS algorithm indicates N-terminal region protein very high probability forming coiled-coil structures often oligomeric proteins. These...
Dominant mutations in the Ret receptor tyrosine kinase lead to familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 significantly alter Ret-signaling properties, but precise mechanisms by which promotes tumorigenesis remain poorly understood. To determine signal transduction pathways required for activity, we analyzed analogous Drosophila ortholog dRet. Overexpressed dRetMEN2 isoforms targeted developing retina led...
Src family kinases regulate multiple cellular processes including proliferation and oncogenesis. C-terminal kinase (Csk) encodes a critical negative regulator of kinases. We demonstrate that the Drosophila melanogaster Csk ortholog, dCsk, functions as tumor suppressor: dCsk mutants display organ overgrowth excess proliferation. Genetic analysis indicates dCsk−/− phenotype results from activation Src, Jun kinase, STAT signal transduction pathways. In particular, blockade function in severely...
Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms potential therapeutic targets glioma (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain model identified dCdk5 as critical regulator. CDK5, human ortholog (79% identity), is aberrantly activated GBMs tightly aligned with both chromosome 7 gains markers affecting...
Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor. In addition to being genetically heterogeneous, GBMs are also immunologically heterogeneous. However, whether differences in immune microenvironment driven by genetic driver mutation unexplored. By leveraging versatile RCAS/ tv‐a somatic gene transfer system, we establish a mouse model for Classical GBM introducing EGFRvIII expression Nestin ‐positive neural stem/progenitor cells adult mice. Along with our previously...
The human c-fes proto-oncogene encodes a cytoplasmic tyrosine kinase (Fes) that is associated with multiple hematopoietic cytokine receptors. Fes autophosphorylation sites may regulate activity and recruit downstream signaling proteins SH2 domains. To localize the sites, full-length deletion mutants lacking either unique N-terminal or domain were autophosphorylated in vitro analyzed by CNBr cleavage. Identical phosphopeptides of 10 4 kDa produced all three proteins, localizing to C-terminal...
Abstract High levels of Src activity are found in a broad spectrum cancers. The roles and its negative regulator Csk have been extensively studied, although results often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression either orthologue resulted apoptotic cell death, but paradoxically, reducing dCsk led over-proliferation tissue overgrowth. Here, we show that Drosophila epithelia situ, signaling determine cellular outcome activation....
Stem cells reside in specialized microenvironments, called niches, that regulate their development and the of progeny. However, maintenance niches are poorly understood. In Drosophila brain, cortex glial provide a niche promotes self-renewal proliferation neural stem cell-like (neuroblasts). central neuroblasts progeny control post-embryonic morphogenesis glia through PDGF-like ligands, this PDGFR receptor tyrosine kinase (RTK) signaling is required for expression DE-cadherin, which sustains...
Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis affect millions of people worldwide. Interferon regulatory factor 5 (IRF5) contains polymorphisms associated with these autoimmune diseases. Two functional are found upstream the IRF5 gene. rs2004640, which is a single nucleotide polymorphism CGGGG insertion/deletion (indel) were studied. uses four different promoters for its first exons: 1A, 1B, 1C, 1D. Each promoter was analyzed,...
Abstract Medulloblastoma is a malignant pediatric tumor that arises from neural progenitors in the cerebellum. Despite five-year survival rate of ~70%, nearly all patients incur adverse side effects current treatment strategies drastically impact quality life. Roughly one-third medulloblastoma are driven by aberrant activation Sonic Hedgehog (SHH) signaling pathway. However, scarcity genetic mutations has led to investigation other mechanisms contributing cancer pathogenicity including...
Glioblastoma (GBM) and lower grade gliomas (LGG) are the most common primary malignant brain tumors resistant to current therapies. Genomic analyses reveal that signature genetic lesions in GBM LGG include copy gain amplification of chromosome 7, amplification, mutation, overexpression receptor tyrosine kinases (RTK) such as EGFR, activating mutations components PI3K pathway. In Drosophila melanogaster, constitutive co-activation RTK signaling glial progenitor cells recapitulates key...
Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults. GBMs are known for their highly invasive and proliferative properties associated with a dismal prognosis (~12-18 months post-diagnosis). Neuroanatomical disparities occurrence of suggest that addition to microenvironmental impacts, cells impacted by cellular molecular diversity across varying regions this nervous system. This idea has been difficult study due lack human-specific models effectively recapitulate...
Abstract Cell state plasticity is retained by all stem-like and differentiated cells within glioblastoma (GBM) tumors. GBM can exploit these state-shifting capacities to evade resist therapeutics. Thus, there a need identify target the regulators of cell transitions. To address this question, we use fully human platform where hiSPC-derived organoids serve as recipient environment host engrafted directly from surgically resected GBMs. This allows us precisely examine how microenvironmental...