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Pancreatic Neoplasms: HELP
Articles by Snorri S. Thorgeirsson
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, Snorri Thorgeirsson wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Loss of PDPK1 abrogates resistance to gemcitabine in label-retaining pancreatic cancer cells. 2018

Li, Dandan / Mullinax, John E / Aiken, Taylor / Xin, Hongwu / Wiegand, Gordon / Anderson, Andrew / Thorgeirsson, Snorri / Avital, Itzhak / Rudloff, Udo. ·Rare Tumor Initiative, Cancer for Cancer Research, National Cancer Institute, Building 10, Room 2B-38E, Bethesda, MD, USA. · Sarcoma Department, Moffitt Cancer Center, Tampa, FL, USA. · Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. · Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Laboratory of Oncology, Center for Molecular Medicine and Department of Molecular Biology and Biochemistry, School of Basic Medicine, Yangtze University, Jingzhou, Hubei, China. · Flow Cytometry Core, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. · Gilead Sciences, Foster City, CA, USA. · Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, USA. · St. Peter's Hospital, Rutgers University, Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA. · Rare Tumor Initiative, Cancer for Cancer Research, National Cancer Institute, Building 10, Room 2B-38E, Bethesda, MD, USA. rudloffu@mail.nih.gov. ·BMC Cancer · Pubmed #30064387.

ABSTRACT: BACKGROUND: Label-retaining cancer cells (LRCC) have been proposed as a model of slowly cycling cancer stem cells (CSC) which mediate resistance to chemotherapy, tumor recurrence, and metastasis. The molecular mechanisms of chemoresistance in LRCC remain to-date incompletely understood. This study aims to identify molecular targets in LRCC that can be exploited to overcome resistance to gemcitabine, a standard chemotherapy agent for the treatment of pancreas cancer. METHODS: LRCC were isolated following Cy5-dUTP staining by flow cytometry from pancreatic cancer cell lines. Gene expression profiles obtained from LRCC, non-LRCC (NLRCC), and bulk tumor cells were used to generate differentially regulated pathway networks. Loss of upregulated targets in LRCC on gemcitabine sensitivity was assessed via RNAi experiments and pharmacological inhibition. Expression patterns of PDPK1, one of the upregulated targets in LRCC, was studied in patients' tumor samples and correlated with pathological variables and clinical outcome. RESULTS: LRCC are significantly more resistant to gemcitabine than the bulk tumor cell population. Non-canonical EGF (epidermal growth factor)-mediated signal transduction emerged as the top upregulated network in LRCC compared to non-LRCC, and knock down of EGF signaling effectors PDPK1 (3-phosphoinositide dependent protein kinase-1), BMX (BMX non-receptor tyrosine kinase), and NTRK2 (neurotrophic receptor tyrosine kinase 2) or treatment with PDPK1 inhibitors increased growth inhibition and induction of apoptosis in response to gemcitabine. Knockdown of PDPK1 preferentially increased growth inhibition and reduced resistance to induction of apoptosis upon gemcitabine treatment in the LRCC vs non-LRCC population. These findings are accompanied by lower expression levels of PDPK1 in tumors compared to matched uninvolved pancreas in surgical resection specimens and a negative association of membranous localization on IHC with high nuclear grade (pā€‰<ā€‰0.01). CONCLUSION: Pancreatic cancer cell-derived LRCC are relatively resistant to gemcitabine and harbor a unique transcriptomic profile compared to bulk tumor cells. PDPK1, one of the members of an upregulated EGF-signaling network in LRCC, mediates resistance to gemcitabine, is found to be dysregulated in pancreas cancer specimens, and might be an attractive molecular target for combination therapy studies.

2 Article CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells. 2014

Jia, Jinping / Bosley, Allen D / Thompson, Abbey / Hoskins, Jason W / Cheuk, Adam / Collins, Irene / Parikh, Hemang / Xiao, Zhen / Ylaya, Kris / Dzyadyk, Marta / Cozen, Wendy / Hernandez, Brenda Y / Lynch, Charles F / Loncarek, Jadranka / Altekruse, Sean F / Zhang, Lizhi / Westlake, Christopher J / Factor, Valentina M / Thorgeirsson, Snorri / Bamlet, William R / Hewitt, Stephen M / Petersen, Gloria M / Andresson, Thorkell / Amundadottir, Laufey T. ·Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota amundadottirl@mail.nih.gov. ·Cancer Res · Pubmed #24648346.

ABSTRACT: Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum where it is likely embedded in the membrane, in accord with multiple predicted transmembrane domains. Overexpression of CLPTM1L enhanced growth of pancreatic cancer cells in vitro (1.3-1.5-fold; PDAY7 < 0.003) and in vivo (3.46-fold; PDAY68 = 0.039), suggesting a role in tumor growth; this effect was abrogated by deletion of two hydrophilic domains. Affinity purification followed by mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II), a protein involved in maintaining cell shape, migration, and cytokinesis. The two proteins colocalized in the cytoplasm and, after treatment with a DNA-damaging agent, at the centrosomes. Overexpression of CLPTM1L and depletion of NMM-II induced aneuploidy, indicating that CLPTM1L may interfere with normal NMM-II function in regulating cytokinesis. Immunohistochemical analysis revealed enhanced staining of CLPTM1L in human pancreatic ductal adenocarcinoma (n = 378) as compared with normal pancreatic tissue samples (n = 17; P = 1.7 Ɨ 10(-4)). Our results suggest that CLPTM1L functions as a growth-promoting gene in the pancreas and that overexpression may lead to an abrogation of normal cytokinesis, indicating that it should be considered as a plausible candidate gene that could explain the effect of pancreatic cancer susceptibility alleles on chr5p15.33.

3 Article An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer. 2013

Jia, Jinping / Parikh, Hemang / Xiao, Wenming / Hoskins, Jason W / Pflicke, Holger / Liu, Xuelu / Collins, Irene / Zhou, Weiyin / Wang, Zhaoming / Powell, John / Thorgeirsson, Snorri S / Rudloff, Udo / Petersen, Gloria M / Amundadottir, Laufey T. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. amundadottirl@mail.nih.gov. ·BMC Med Genomics · Pubmed #24053169.

ABSTRACT: BACKGROUND: Pancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities. METHODS: To begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas. RESULTS: By RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues. CONCLUSIONS: As aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells.

4 Article Comparative testing of various pancreatic cancer stem cells results in a novel class of pancreatic-cancer-initiating cells. 2012

Jaiswal, Kshama R / Xin, Hong-Wu / Anderson, Andrew / Wiegand, Gordon / Kim, Bo / Miller, Tyler / Hari, Danielle / Ray, Satyajit / Koizumi, Tomotake / Rudloff, Udo / Thorgeirsson, Snorri S / Avital, Itzhak. ·Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ·Stem Cell Res · Pubmed #22963768.

ABSTRACT: No systemic therapy is effective against pancreatic cancer (PC). Pancreatic cancer stem cells (PCSC) are hypothesized to account for therapeutic resistance. Several PCSC subpopulations were reported, each characterized by different markers. To be able to target PCSC, we sought to better define this putative heterogeneity. Therefore, we tested most of the known putative PCSC markers in established and fresh tumor cell lines. CD20, CD24, CD44, CD133, CD184 (CXCR4), CD326 (EpCam, ESA), Sox-2, OCT 3/4, and the side-population (SP) were tested in five PC cell lines, and the effects of confluency, hypoxia, radiation, and gemcitabine on the SP. The testing phase suggested several putative PCSC populations that were further tested and validated for their tumor-initiating capacity against known PCSC in 3 established and 1 fresh PC cell lines. Cell surface and intracellular markers showed significant variability among cell lines. SP was the only common marker in all cell lines and consistently less than 1%. SP response to confluence, hypoxia, radiation, and gemcitabine was inconsistent between cell lines. The initial testing phase suggested that SP/CD44-CD24-CD326+ cells might be a novel PCSC subpopulation. Tumor initiation capacity tests in nude mice confirmed their increased tumorigenicity over previously reported PCSC. Our data better define the heterogeneity of reported PCSC in cell lines tested in this study. We propose that prior to targeting PC via PCSC, one will need to gain more insight into this heterogeneity. Finally, we show that SP/CD44-CD24-CD326+ cells are a novel subpopulation of pancreatic cancer tumor initiating cells. Further mechanistic studies may lead to better targeting of PC via targeting this novel PCSC.