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Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cells.
Cigliola V, Ghila L, Thorel F, van Gurp L, Baronnier D, Oropeza D, Gupta S, Miyatsuka T, Kaneto H, Magnuson MA, Osipovich AB, Sander M, Wright CEV, Thomas MK, Furuyama K, Chera S, Herrera PL
(2018) Nat Cell Biol 20: 1267-1277
MeSH Terms: Animals, Cell Differentiation, Cell Plasticity, Cell Proliferation, Female, Glucagon-Secreting Cells, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mice, Transgenic, Signal Transduction, Smoothened Receptor
Show Abstract · Added November 6, 2018
The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.
2 Communities
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16 MeSH Terms
Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis.
Stoletov K, Willetts L, Paproski RJ, Bond DJ, Raha S, Jovel J, Adam B, Robertson AE, Wong F, Woolner E, Sosnowski DL, Bismar TA, Wong GK, Zijlstra A, Lewis JD
(2018) Nat Commun 9: 2343
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Chick Embryo, Collagen, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Phenotype, Prostatic Neoplasms, RNA Interference, RNA, Small Interfering
Show Abstract · Added April 10, 2019
Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.
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MeSH Terms
Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.
Song W, Hwang Y, Youngblood VM, Cook RS, Balko JM, Chen J, Brantley-Sieders DM
(2017) Oncogene 36: 5620-5630
MeSH Terms: Animals, Benzamides, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Ephrin-A2, Female, Gene Knockdown Techniques, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasm Recurrence, Local, Niacinamide, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-myb, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added March 14, 2018
Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.
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2 Members
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20 MeSH Terms
Altered TGF-α/β signaling drives cooperation between breast cancer cell populations.
Franco OE, Tyson DR, Konvinse KC, Udyavar AR, Estrada L, Quaranta V, Crawford SE, Hayward SW
(2016) FASEB J 30: 3441-3452
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Transformation, Neoplastic, Epithelium, Humans, Mice, SCID, Signal Transduction, Transforming Growth Factor alpha, Transforming Growth Factor beta
Show Abstract · Added May 5, 2017
The role of tumor heterogeneity in regulating disease progression is poorly understood. We hypothesized that interactions between subpopulations of cancer cells can affect the progression of tumors selecting for a more aggressive phenotype. We developed an in vivo assay based on the immortalized nontumorigenic breast cell line MCF10A and its Ras-transformed derivatives AT1 (mildly tumorigenic) and CA1d (highly tumorigenic). CA1d cells outcompeted MCF10A, forming invasive tumors. AT1 grafts were approximately 1% the size of CA1d tumors when initiated using identical cell numbers. In contrast, CA1d/AT1 mixed tumors were larger than tumors composed of AT1 alone (100-fold) or CA1d (3-fold), suggesting cooperation in tumor growth. One of the mechanisms whereby CA1d and AT1 were found to cooperate was by modulation of TGF-α and TGF-β signaling. Both of these molecules were sufficient to induce changes in AT1 proliferative potential in vitro. Reisolation of AT1 tumor-derived (AT1) cells from these mixed tumors revealed that AT1 cells grew in vivo, forming tumors as large as tumorigenic CA1d cells. Cooperation between subpopulations of cancer epithelium is an understudied mechanism of tumor growth and invasion that may have implications on tumor resistance to current therapies.-Franco, O. E., Tyson, D. R., Konvinse, K. C., Udyavar, A. R., Estrada, L., Quaranta, V., Crawford, S. E., Hayward, S. W. Altered TGF-α/β signaling drives cooperation between breast cancer cell populations.
© FASEB.
1 Communities
1 Members
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11 MeSH Terms
Activated tumor cell integrin αvβ3 cooperates with platelets to promote extravasation and metastasis from the blood stream.
Weber MR, Zuka M, Lorger M, Tschan M, Torbett BE, Zijlstra A, Quigley JP, Staflin K, Eliceiri BP, Krueger JS, Marchese P, Ruggeri ZM, Felding BH
(2016) Thromb Res 140 Suppl 1: S27-36
MeSH Terms: Animals, Blood Platelets, Cell Line, Tumor, Cell Movement, Humans, Integrin alphaVbeta3, Mice, SCID, Neoplasm Metastasis, Neoplastic Cells, Circulating
Show Abstract · Added April 6, 2017
Metastasis is the main cause of death in cancer patients, and understanding mechanisms that control tumor cell dissemination may lead to improved therapy. Tumor cell adhesion receptors contribute to cancer spreading. We noted earlier that tumor cells can expressing the adhesion receptor integrin αvβ3 in distinct states of activation, and found that cells which metastasize from the blood stream express it in a constitutively high affinity form. Here, we analyzed steps of the metastatic cascade in vivo and asked, when and how the affinity state of integrin αvβ3 confers a critical advantage to cancer spreading. Following tumor cells by real time PCR, non-invasive bioluminescence imaging, intravital microscopy and histology allowed us to identify tumor cell extravasation from the blood stream as a rate-limiting step supported by high affinity αvβ3. Successful transendothelial migration depended on cooperation between tumor cells and platelets involving the high affinity tumor cell integrin and release of platelet granules. Thus, this study identifies the high affinity conformer of integrin αvβ3 and its interaction with platelets as critical for early steps during hematogenous metastasis and target for prevention of metastatic disease.
© 2016 Elsevier Ltd. All rights reserved.
1 Communities
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9 MeSH Terms
Anti-Tumor Effects after Adoptive Transfer of IL-12 Transposon-Modified Murine Splenocytes in the OT-I-Melanoma Mouse Model.
Galvan DL, O'Neil RT, Foster AE, Huye L, Bear A, Rooney CM, Wilson MH
(2015) PLoS One 10: e0140744
MeSH Terms: Adoptive Transfer, Animals, DNA Transposable Elements, HeLa Cells, Humans, Interleukin-12, Melanoma, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasms, Experimental, Spleen, T-Lymphocytes
Show Abstract · Added March 7, 2016
Adoptive transfer of gene modified T cells provides possible immunotherapy for patients with cancers refractory to other treatments. We have previously used the non-viral piggyBac transposon system to gene modify human T cells for potential immunotherapy. However, these previous studies utilized adoptive transfer of modified human T cells to target cancer xenografts in highly immunodeficient (NOD-SCID) mice that do not recapitulate an intact immune system. Currently, only viral vectors have shown efficacy in permanently gene-modifying mouse T cells for immunotherapy applications. Therefore, we sought to determine if piggyBac could effectively gene modify mouse T cells to target cancer cells in a mouse cancer model. We first demonstrated that we could gene modify cells to express murine interleukin-12 (p35/p40 mIL-12), a transgene with proven efficacy in melanoma immunotherapy. The OT-I melanoma mouse model provides a well-established T cell mediated immune response to ovalbumin (OVA) positive B16 melanoma cells. B16/OVA melanoma cells were implanted in wild type C57Bl6 mice. Mouse splenocytes were isolated from C57Bl6 OT-I mice and were gene modified using piggyBac to express luciferase. Adoptive transfer of luciferase-modified OT-I splenocytes demonstrated homing to B16/OVA melanoma tumors in vivo. We next gene-modified OT-I cells to express mIL-12. Adoptive transfer of mIL-12-modified mouse OT-I splenocytes delayed B16/OVA melanoma tumor growth in vivo compared to control OT-I splenocytes and improved mouse survival. Our results demonstrate that the piggyBac transposon system can be used to gene modify splenocytes and mouse T cells for evaluating adoptive immunotherapy strategies in immunocompetent mouse tumor models that may more directly mimic immunotherapy applications in humans.
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13 MeSH Terms
Outer surface protein OspC is an antiphagocytic factor that protects Borrelia burgdorferi from phagocytosis by macrophages.
Carrasco SE, Troxell B, Yang Y, Brandt SL, Li H, Sandusky GE, Condon KW, Serezani CH, Yang XF
(2015) Infect Immun 83: 4848-60
MeSH Terms: Animals, Antigens, Bacterial, B-Lymphocytes, Bacterial Outer Membrane Proteins, Borrelia burgdorferi, Cell Line, Female, Gene Expression Regulation, Bacterial, Genes, Reporter, Green Fluorescent Proteins, Humans, Immune Evasion, Killer Cells, Natural, Lyme Disease, Macrophages, Peritoneal, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neutrophils, T-Lymphocytes
Show Abstract · Added May 4, 2017
Outer surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2rγ(null) mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms
A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, Escarpe PA, Hampl J, Laysang A, Liu D, Lopez-Molina J, Milton M, Park A, Pysz MA, Shao H, Slingerland B, Torgov M, Williams SA, Foord O, Howard P, Jassem J, Badzio A, Czapiewski P, Harpole DH, Dowlati A, Massion PP, Travis WD, Pietanza MC, Poirier JT, Rudin CM, Stull RA, Dylla SJ
(2015) Sci Transl Med 7: 302ra136
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Female, Humans, Immunoconjugates, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Membrane Proteins, Mice, Mice, Inbred NOD, Mice, SCID, Neuroendocrine Tumors, Xenograft Model Antitumor Assays
Show Abstract · Added February 16, 2016
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.
Copyright © 2015, American Association for the Advancement of Science.
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14 MeSH Terms
Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A.
Ra H, González-González E, Uddin MJ, King BL, Lee A, Ali-Khan I, Marnett LJ, Tang JY, Contag CH
(2015) Neoplasia 17: 201-7
MeSH Terms: Animals, Carcinoma, Basal Cell, Cyclooxygenase 2 Inhibitors, Indoles, Mice, Mice, SCID, Optical Imaging, Rhodamines, Skin Neoplasms
Show Abstract · Added February 22, 2016
Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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9 MeSH Terms
Tumor-secreted Hsp90 subverts polycomb function to drive prostate tumor growth and invasion.
Nolan KD, Franco OE, Hance MW, Hayward SW, Isaacs JS
(2015) J Biol Chem 290: 8271-82
MeSH Terms: Animals, Antigens, CD, Cadherins, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression, Gene Expression Regulation, Neoplastic, HEK293 Cells, HSP90 Heat-Shock Proteins, Humans, MAP Kinase Signaling System, Male, Mice, SCID, Neoplasm Invasiveness, Neoplasm Transplantation, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Prostatic Neoplasms, Tumor Burden
Show Abstract · Added February 19, 2015
Prostate cancer remains the second highest contributor to male cancer-related lethality. The transition of a subset of tumors from indolent to invasive disease is associated with a poor clinical outcome. Activation of the epithelial to mesenchymal transition (EMT) genetic program is a major risk factor for cancer progression. We recently reported that secreted extracellular Hsp90 (eHsp90) initiates EMT in prostate cancer cells, coincident with its enhanced expression in mesenchymal models. Our current work substantially extended these findings in defining a pathway linking eHsp90 signaling to EZH2 function, a methyltransferase of the Polycomb repressor complex. EZH2 is also implicated in EMT activation, and its up-regulation represents one of the most frequent epigenetic alterations during prostate cancer progression. We have now highlighted a novel epigenetic function for eHsp90 via its modulation of EZH2 expression and activity. Mechanistically, eHsp90 initiated sustained activation of MEK/ERK, a signal critical for facilitating EZH2 transcriptional up-regulation and recruitment to the E-cadherin promoter. We further demonstrated that an eHsp90-EZH2 pathway orchestrates an expanded repertoire of EMT-related events including Snail and Twist expression, tumor cell motility, and anoikis resistance. To evaluate the role of eHsp90 in vivo, eHsp90 secretion was stably enforced in a prostate cancer cell line resembling indolent disease. Remarkably, eHsp90 was sufficient to induce tumor growth, suppress E-cadherin, and initiate localized invasion, events that are exquisitely dependent upon EZH2 function. In summary, our findings illuminate a hitherto unknown epigenetic function for eHsp90 and support a model wherein tumor eHsp90 functions as a rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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21 MeSH Terms