10 results on '"Molyneux SD"'
Search Results
2. RANKL blockade prevents and treats aggressive osteosarcomas.
- Author
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Chen Y, Di Grappa MA, Molyneux SD, McKee TD, Waterhouse P, Penninger JM, and Khokha R
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Gene Deletion, Humans, Mice, Neoplasm Invasiveness, Organ Specificity, Osteoblasts metabolism, Osteosarcoma genetics, Osteosarcoma therapy, PTEN Phosphohydrolase metabolism, RANK Ligand metabolism, Retinoblastoma Protein genetics, Retinoblastoma Protein metabolism, Signal Transduction, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Osteosarcoma metabolism, Osteosarcoma pathology, RANK Ligand antagonists & inhibitors
- Abstract
Osteosarcoma (OS) is the most common primary bone cancer, which occurs primarily in children and adolescents, severely affecting survivors' quality of life. Despite its chemosensitivity and treatment advances, long-term survival rates for OS patients have stagnated over the last 20 years. Thus, it is necessary to develop new molecularly targeted therapies for this metastatic bone cancer. Mutations in TP53 and RB are linked to OS predisposition and to the evolution of spontaneous OS. We established receptor activator of nuclear factor κB ligand (RANKL) as a therapeutic target for suppression and prevention of OS. Combined conditional osteoblast-specific deletions of Rb, p53, and the protein kinase A (PKA) regulatory subunit Prkar1α genes in genetically engineered mouse models (GEMMs) generate aggressive osteosarcomas, characterized by PKA, RANKL, and osteoclast hyperactivity. Whole-body Rankl deletion completely abrogates tumorigenesis. Although osteoblastic Rank deletion has little effect, osteoclastic Rank deletion delays tumorigenesis and prolongs life span. The latter is associated with inactivation of osteoclastogenesis and up-regulation of the tumor suppressor phosphatase and tensin homolog (PTEN). Further, we use these GEMMs as preclinical platforms to show that RANKL blockade with RANK-Fc arrests tumor progression and improves survival and also inhibits lung metastasis. Moreover, preemptive administration of RANK-Fc completely prevents tumorigenesis in mice highly predisposed to this aggressive cancer. Denosumab, a fully human monoclonal antibody against RANKL, is currently used to treat patients with osteoporosis or bone metastases. Our studies provide a strong rationale to consider RANKL blockade for the treatment and prevention of aggressive RANKL-overexpressing OS in humans., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
- Full Text
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3. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.
- Author
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Moriarity BS, Otto GM, Rahrmann EP, Rathe SK, Wolf NK, Weg MT, Manlove LA, LaRue RS, Temiz NA, Molyneux SD, Choi K, Holly KJ, Sarver AL, Scott MC, Forster CL, Modiano JF, Khanna C, Hewitt SM, Khokha R, Yang Y, Gorlick R, Dyer MA, and Largaespada DA
- Subjects
- Animals, Bone Neoplasms pathology, Carcinogenesis genetics, Cell Line, Tumor, DNA Transposable Elements, Dogs, Genetic Predisposition to Disease, Genomic Instability, Humans, Mice, Transgenic, Mutagenesis, Insertional, Osteosarcoma secondary, PTEN Phosphohydrolase genetics, Semaphorins genetics, Semaphorins metabolism, Tumor Suppressor Protein p53 genetics, Bone Neoplasms genetics, Osteosarcoma genetics
- Abstract
Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.
- Published
- 2015
- Full Text
- View/download PDF
4. PKA signaling drives mammary tumorigenesis through Src.
- Author
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Beristain AG, Molyneux SD, Joshi PA, Pomroy NC, Di Grappa MA, Chang MC, Kirschner LS, Privé GG, Pujana MA, and Khokha R
- Subjects
- Androstadienes pharmacology, Animals, Cell Line, Cell Proliferation, Cell Transformation, Neoplastic pathology, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics, Dasatinib, Epithelial Cells metabolism, Epithelial Cells pathology, Female, Humans, Mammary Glands, Animal metabolism, Mammary Neoplasms, Experimental metabolism, Mice, Phosphorylation, Pyrimidines pharmacology, Signal Transduction, Thiazoles pharmacology, Wortmannin, src-Family Kinases genetics, Cell Transformation, Neoplastic metabolism, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit metabolism, Mammary Glands, Animal pathology, Mammary Neoplasms, Experimental pathology, src-Family Kinases metabolism
- Abstract
Protein kinase A (PKA) hyperactivation causes hereditary endocrine neoplasias; however, its role in sporadic epithelial cancers is unknown. Here, we show that heightened PKA activity in the mammary epithelium generates tumors. Mammary-restricted biallelic ablation of Prkar1a, which encodes for the critical type-I PKA regulatory subunit, induced spontaneous breast tumors characterized by enhanced type-II PKA activity. Downstream of this, Src phosphorylation occurs at residues serine-17 and tyrosine-416 and mammary cell transformation is driven through a mechanism involving Src signaling. The phenotypic consequences of these alterations consisted of increased cell proliferation and, accordingly, expansion of both luminal and basal epithelial cell populations. In human breast cancer, low PRKAR1A/high SRC expression defines basal-like and HER2 breast tumors associated with poor clinical outcome. Together, the results of this study define a novel molecular mechanism altered in breast carcinogenesis and highlight the potential strategy of inhibiting SRC signaling in treating this cancer subtype in humans.
- Published
- 2015
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5. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.
- Author
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Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, Yung KY, Brenner D, Knobbe-Thomsen CB, Cox MA, Elia A, Berger T, Cescon DW, Adeoye A, Brüstle A, Molyneux SD, Mason JM, Li WY, Yamamoto K, Wakeham A, Berman HK, Khokha R, Done SJ, Kavanagh TJ, Lam CW, and Mak TW
- Subjects
- Animals, Breast Neoplasms pathology, Carcinogenesis, Female, Glutamate-Cysteine Ligase metabolism, Glutathione genetics, Humans, Mammary Neoplasms, Animal drug therapy, Mammary Neoplasms, Animal pathology, Mice, Mice, Transgenic, Thioredoxins metabolism, Antioxidants metabolism, Breast Neoplasms genetics, Glutamate-Cysteine Ligase genetics, Mammary Neoplasms, Animal genetics
- Abstract
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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6. Human somatic cell mutagenesis creates genetically tractable sarcomas.
- Author
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Molyneux SD, Waterhouse PD, Shelton D, Shao YW, Watling CM, Tang QL, Harris IS, Dickson BC, Tharmapalan P, Sandve GK, Zhang X, Bailey SD, Berman H, Wunder JS, Izsvák Z, Lupien M, Mak TW, and Khokha R
- Subjects
- Cell Line, DNA Transposable Elements, Genetic Vectors genetics, Genome, Human, HEK293 Cells, Humans, RNA-Binding Proteins genetics, Retroviridae genetics, Mutagenesis, Insertional, Sarcoma genetics
- Abstract
Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis.
- Published
- 2014
- Full Text
- View/download PDF
7. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.
- Author
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Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T, and Khokha R
- Subjects
- ADAM Proteins metabolism, ADAM10 Protein, Amyloid Precursor Protein Secretases metabolism, Animals, Cell Line, Tumor, Cell Movement, Exosomes physiology, Female, Fibroblasts pathology, Humans, Lung Neoplasms enzymology, Mammary Neoplasms, Experimental enzymology, Membrane Proteins metabolism, Metalloendopeptidases metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Transplantation, Phenotype, Signal Transduction, Tissue Inhibitor of Metalloproteinases deficiency, Tumor Burden, Fibroblasts metabolism, Lung Neoplasms secondary, Mammary Neoplasms, Experimental pathology, Tissue Inhibitor of Metalloproteinases genetics
- Abstract
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.
- Published
- 2014
- Full Text
- View/download PDF
8. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival.
- Author
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Gorrini C, Baniasadi PS, Harris IS, Silvester J, Inoue S, Snow B, Joshi PA, Wakeham A, Molyneux SD, Martin B, Bouwman P, Cescon DW, Elia AJ, Winterton-Perks Z, Cruickshank J, Brenner D, Tseng A, Musgrave M, Berman HK, Khokha R, Jonkers J, Mak TW, and Gauthier ML
- Subjects
- Animals, BRCA1 Protein deficiency, BRCA1 Protein genetics, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Line, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Epithelial Cells drug effects, Epithelial Cells metabolism, Estrogens pharmacology, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Mammary Glands, Animal metabolism, Mammary Glands, Animal pathology, Mice, Mutation, NAD(P)H Dehydrogenase (Quinone) genetics, NAD(P)H Dehydrogenase (Quinone) metabolism, NF-E2-Related Factor 2 genetics, Oxidative Stress, Protein Binding, Protein Stability, Reactive Oxygen Species metabolism, Ubiquitination, Antioxidants metabolism, BRCA1 Protein metabolism, Cell Survival genetics, NF-E2-Related Factor 2 metabolism, Signal Transduction
- Abstract
Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
- Published
- 2013
- Full Text
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9. Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis.
- Author
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Murthy A, Shao YW, Narala SR, Molyneux SD, Zúñiga-Pflücker JC, and Khokha R
- Subjects
- ADAM Proteins genetics, ADAM Proteins immunology, ADAM17 Protein, Animals, Cell Proliferation, Epidermal Cells, Gene Deletion, Humans, Inflammation, Keratinocytes immunology, Mice, Mice, Inbred C57BL, Models, Biological, Receptors, Notch immunology, Signal Transduction, ADAM Proteins metabolism, Cytokines metabolism, Epidermis enzymology, Epidermis immunology, Granulocyte Precursor Cells cytology, Receptors, Notch metabolism
- Abstract
Epithelial cells of mucosal tissues provide a barrier against environmental stress, and keratinocytes are key decision makers for immune cell function in the skin. Currently, epithelial signaling networks that instruct barrier immunity remain uncharacterized. Here we have shown that keratinocyte-specific deletion of a disintegrin and metalloproteinase 17 (Adam17) triggers T helper 2 and/or T helper 17 (Th2 and/or Th17) cell-driven atopic dermatitis and myeloproliferative disease. In vivo and in vitro deficiency of ADAM17 dampened Notch signaling, increasing production of the Th2 cell-polarizing cytokine TSLP and myeloid growth factor G-CSF. Ligand-independent Notch activation was identified as a regulator of AP-1 transcriptional activity, with Notch antagonizing c-Fos recruitment to the promoters of Tslp and Csf3 (G-CSF). Further, skin inflammation was rescued and myeloproliferation ameliorated by delivery of active Notch to Adam17(-)(/-) epidermis. Our findings uncover an essential role of ADAM17 in the adult epidermis, demonstrating a gatekeeper function of the ADAM17-Notch-c-Fos triad in barrier immunity., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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10. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice.
- Author
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Molyneux SD, Di Grappa MA, Beristain AG, McKee TD, Wai DH, Paderova J, Kashyap M, Hu P, Maiuri T, Narala SR, Stambolic V, Squire J, Penninger J, Sanchez O, Triche TJ, Wood GA, Kirschner LS, and Khokha R
- Subjects
- Animals, Disease Models, Animal, Gene Deletion, Mice, Mice, Transgenic, Phenotype, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics, Genes, Tumor Suppressor, Osteosarcoma genetics
- Abstract
Some cancers have been stratified into subclasses based on their unique involvement of specific signaling pathways. The mapping of human cancer genomes is revealing a vast number of somatic alterations; however, the identification of clinically relevant molecular tumor subclasses and their respective driver genes presents challenges. This information is key to developing more targeted and personalized cancer therapies. Here, we generate a new mouse model of genomically unstable osteosarcoma (OSA) that phenocopies the human disease. Integrative oncogenomics pinpointed cAMP-dependent protein kinase type I, alpha regulatory subunit (Prkar1a) gene deletions at 11qE1 as a recurrent genetic trait for a molecularly distinct subclass of mouse OSA featuring RANKL overexpression. Using mouse genetics, we established that Prkar1a is a bone tumor suppressor gene capable of directing subclass development and driving RANKL overexpression during OSA tumorigenesis. Finally, we uncovered evidence for a PRKAR1A-low subset of human OSA with distinct clinical behavior. Thus, tumor subclasses develop in mice and can potentially provide information toward the molecular stratification of human cancers.
- Published
- 2010
- Full Text
- View/download PDF
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