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DNA methylation in PDX

Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
September 7, 2016: Gynecologic Oncology
Hye-Young Min, Su-Chan Lee, Jong Kyu Woo, Hyun Jin Jung, Kwan Hee Park, Hae Min Jeong, Seung Yeob Hyun, Jaebeom Cho, Wooin Lee, Ji Eun Park, So Jung Kwon, Hyo-Jong Lee, Xiao Ni, Young Kee Shin, Faye M Johnson, Madeleine Duvic, Ho-Young Lee
PURPOSE: Histone deacetylase inhibitors (HDIs) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study. EXPERIMENTAL DESIGN: The methylation status of CCCTC binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing...
August 31, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Petra Ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jóźwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen, Jelle Wesseling, Jos Jonkers
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined...
November 2016: Journal of the National Cancer Institute
Brittany Kleb, Marcos R H Estécio, Jiexin Zhang, Vassiliki Tzelepi, Woonbok Chung, Jaroslav Jelinek, Nora M Navone, Salahaldin Tahir, Victor E Marquez, Jean-Pierre Issa, Sankar Maity, Ana Aparicio
Small cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection and treatment with effective chemotherapy are needed. Our studies in patient tumor-derived xenografts (PDX) revealed that AR-negative SCPC (AR(-)SCPC) expresses neural development genes instead of the prostate luminal epithelial genes characteristic of AR-positive castration-resistant adenocarcinomas (AR(+)ADENO)...
March 3, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Shiv K Gupta, Sani H Kizilbash, Brett L Carlson, Ann C Mladek, Felix Boakye-Agyeman, Katrina K Bakken, Jenny L Pokorny, Mark A Schroeder, Paul A Decker, Ling Cen, Jeanette E Eckel-Passow, Gobinda Sarkar, Karla V Ballman, Joel M Reid, Robert B Jenkins, Roeland G Verhaak, Erik P Sulman, Gaspar J Kitange, Jann N Sarkaria
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided...
May 2016: Journal of the National Cancer Institute
Masaki Nagaya, Yoshikazu Arai, Hitomi Matsunari, Michiyo Honda, Kazuaki Nakano, Miki Maehara, Naomi Sugimoto, Mirina Kobayashi, Rieko Sakai, Yoshinori Asano, Masahito Watanabe, Kazuhiro Umeyama, Hiroshi Nagashima
OBJECTIVE: The present study aimed to establish a new method to evaluate the influence of immunosuppressive drugs on pancreatic islets in short-term in vitro cultures using epigenetic analysis in a 3-dimensional culture. METHODS: For this purpose, we selected (a) a 3-dimensional culture system utilizing thermoreversible gelation polymer, (b) pancreatic duodenal homeobox-1 (pdx-1)-Venus transgenic pigs expressing the green fluorescent protein, (c) FK506 as an immunosuppressive drug of the evaluation, and (d) the bisulfite sequencing technique to evaluate the methylation levels of pdx-1 and insulin genes...
July 2015: Pancreas
J T Poirier, E E Gardner, N Connis, A L Moreira, E de Stanchina, C L Hann, C M Rudin
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations...
November 26, 2015: Oncogene
Monique D Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumitra Ananda, Marisol Harrell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B Fox, Jeffrey B Kerr, Karla J Hutt, Scott H Kaufmann, Australian Ovarian Cancer Study, Elizabeth M Swisher, David D Bowtell, Matthew J Wakefield, Clare L Scott
INTRODUCTION: Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses. METHODS: We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity...
May 2014: Molecular Oncology
Beatrice T Yang, Tasnim A Dayeh, Petr A Volkov, Clare L Kirkpatrick, Siri Malmgren, Xingjun Jing, Erik Renström, Claes B Wollheim, Marloes Dekker Nitert, Charlotte Ling
Mutations in pancreatic duodenal homeobox 1 (PDX-1) can cause a monogenic form of diabetes (maturity onset diabetes of the young 4) in humans, and silencing Pdx-1 in pancreatic β-cells of mice causes diabetes. However, it is not established whether epigenetic alterations of PDX-1 influence type 2 diabetes (T2D) in humans. Here we analyzed mRNA expression and DNA methylation of PDX-1 in human pancreatic islets from 55 nondiabetic donors and nine patients with T2D. We further studied epigenetic regulation of PDX-1 in clonal β-cells...
July 2012: Molecular Endocrinology
Rudolf T Pillich, Gianfranco Scarsella, Gianfranco Risuleo
AIM: To explore the possibility that PDX-1 gene is reactivated as a consequence of molecular events that occur during liver regeneration. METHODS: Rat hepatocytes were maintained in DMEM-F12, 10% fetal bovine serum (FBS), penicillin/streptomycin and geneticin when applicable. Rat insulinoma RIN 1046-38 cells were maintained in M-199-10% FBS and penicillin/streptomycin. The final concentration of glucose was 11.1 mmol/L. During regeneration, lateral and medial liver lobes of adult male Wistar rats were surgically removed, with up 70% loss of liver mass...
September 26, 2010: World Journal of Biological Chemistry
Aiping Fang, Yue Zhang, Mingyue Li, Hui Guo, Xiaofang Yu, Furong Li, Hong Hu
The effects of epigenetic modification on the differentiation of islet cells and the expression of associated genes (Pdx-1, Pax4, MafA, and Nkx6.1, etc) were investigated. The promoter methylation status of islet differentiation-associated genes (Pdx-1, Pax4, MafA and Nkx6.1), Oct4 and MLH1 genes of mouse embryonic stem cells, NIH3T3 cells and NIT-1 cells were profiled by methylated DNA immunoprecipitation, real-time quantitative PCR (MeDIP-qPCR) techniques. The histone modification status of these genes promoter region in different cell types was also measured by using chromatin immunoprecipitation real-time quantitative PCR methods...
February 2011: Journal of Huazhong University of Science and Technology. Medical Sciences
Samir Jabari, Matthias Meissnitzer, Karl Quint, Susanne Gahr, Till Wissniowski, Eckhart G Hahn, Daniel Neureiter, Matthias Ocker
Tumor cells have the capability to trans- and to dedifferentiate, for example by reactivating embryonic development genes and stem cell characteristics. The aim of our study was to show the differential expression of stem- and progenitor cell markers in human hepatocellular carcinoma cell lines (HCC). Different human HCC cell lines (HUH7, HUH7 5-15, HUH7 pcDNA3.1, Hep3B and HepG2) were cultured under standard conditions in vitro or implanted subcutaneously (5x10(6) cells) in male NMRI mice. Specimens were characterized by quantitative real-time PCR, Western blotting, methylation-specific PCR and immunohistochemistry for markers of differentiation (cytokeratins, vimentin), embryonic development or stem cells (PTC, PDX-1, SHH, Thy1, c-kit, CD34, beta-catenin, Ki-67)...
July 2009: International Journal of Oncology
Joshua Francis, Swarup K Chakrabarti, James C Garmey, Raghavendra G Mirmira
Expression of the insulin gene is nearly exclusive to the beta cells of the pancreatic islets. Although the sequence-specific transcription factors that regulate insulin expression have been well studied, the interrelationship between these factors, chromatin structure, and transcriptional elongation by RNA polymerase II (pol II) has remained undefined. In this regard, recent studies have begun to establish a role for the methylation of histone H3 in the initiation or elongation of transcription by pol II. To determine a role for the transcriptional activator Pdx-1 in the maintenance of chromatin structure and pol II recruitment at the insulin gene, we performed small interfering RNA-mediated knockdown of Pdx-1 in betaTC3 cells and subsequently studied histone modifications and pol II recruitment by chromatin immunoprecipitation...
October 28, 2005: Journal of Biological Chemistry
Cyrus C Martin, James K Oeser, Richard M O'Brien
Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is selectively expressed in islet beta cells and is a major autoantigen in a mouse model of type I diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression through transient transfection of islet-derived betaTC-3 cells revealed that a promoter region, located between -273 and -254, is essential for high IGRP-CAT fusion gene expression. The sequence of this promoter region does not match that for any known islet-enriched transcription factor...
August 13, 2004: Journal of Biological Chemistry
R Rimseliene, A Janulaitis
The role of two sequence motifs (SM) as putative cleavage catalytic centers (77)PDX(13)EAK (SM I) and (811)PDX(20)DQK (SM II) of type IV restriction endonuclease Eco57I was studied by site-directed mutational analysis. Substitutions within SM I; D78N, D78A, D78K, and E92Q reduced cleavage activity of Eco57I to a level undetectable both in vivo and in vitro. Residual endonucleolytic activity of the E92Q mutant was detected only when the Mg(2+) in the standard reaction mixture was replaced with Mn(2+). The mutants D78N and E92Q retained the ability to interact with DNA specifically...
March 30, 2001: Journal of Biological Chemistry
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