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Molecular Oncology

Moamen Bydoun, Andra Sterea, Henry Liptay, Andrea Uzans, Weei-Yuarn Huang, Gloria J Rodrigues, Ian C G Weaver, Hong Gu, David M Waisman
Pancreatic cancer is arguably the deadliest cancer type. The efficacy of current therapies is often hindered by the inability to predict patient outcome. As such, the development of tools for early detection and risk prediction is key for improving outcome and quality of life. Here, we introduce the plasminogen receptor S100A10 as a novel predictive biomarker and a driver of pancreatic tumor growth and invasion. We demonstrated that S100A10 mRNA and protein are overexpressed in human pancreatic tumors compared to normal ducts and non-ductal stroma...
July 16, 2018: Molecular Oncology
Christian Breunig, Nese Erdem, Alexander Bott, Julia Franziska Greiwe, Eileen Reinz, Stephan Bernhardt, Chiara Giacomelli, Astrid Wachter, Eva Johanna Kanthelhardt, Tim Beißbarth, Martina Vetter, Stefan Wiemann
Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genome-wide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is co-regulated with TGFBR2...
July 13, 2018: Molecular Oncology
Xuejie Min, Jun Wen, Li Zhao, Kaiying Wang, Qingli Li, Gang Huang, Jianjun Liu, Xiaoping Zhao
Although identified as a growth factor, the mechanism by which hepatoma-derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA-sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF-induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor...
July 13, 2018: Molecular Oncology
Willemijne Schrijver, Karianne Schuurman, Annelot van Rossum, Marjolein Droog, Carmen Jeronimo, Sofia Salta, Rui Henrique, Jelle Wesseling, Cathy Moelans, Sabine C Linn, Michel van de Heuvel, Paul van Diest, Wilbert Zwart
Estrogen receptor alpha (ERα)-driven early breast cancer is often treated with antihormonal regimens. However, resistance to treatment is common, leading to metastatic disease. ERα activity requires the functional involvement of pioneer factors FOXA1 and GATA3, which enable ERα chromatin binding and are crucial for ERα-driven cell proliferation. FOXA1 was found increased in metastatic breast cancers in relation to the primary tumor, but a comprehensive clinical assessment thereof, in relation to different metastatic sites and endocrine therapy usage, is currently lacking...
July 4, 2018: Molecular Oncology
Hersi Mohamed Hersi, Nina Raulf, Joop Gaken, Najeem'deen Folarin, Mahvash Tavassoli
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over 50% of patients. There is therefore a crucial need for predictive and/or prognostic biomarkers to allow treatment stratification for individual patients. One class of biomarkers that has recently gained importance are microRNAs (miRNAs). MiRNAs are small, non-coding molecules which regulate gene expression post transcriptionally. We performed miRNA expression profiling of a cohort of head and neck tumours with known clinical outcomes...
June 30, 2018: Molecular Oncology
Xiaoqiang Zhu, Xianglong Tian, Tiantian Sun, Chenyang Yu, Yingying Cao, Tingting Yan, Chaoqin Shen, Yanwei Lin, Jing-Yuan Fang, Jie Hong, Haoyan Chen
Although several prognostic signatures have been developed for gastric cancer (GC), the utility of these tools is limited in clinical practice due to lack of validation with large and multiple independent cohorts, or lack of a statistical test to determine the robustness of the predictive models. Here, a prognostic signature was constructed using a LASSO Cox regression model and a training dataset with 300 GC patients. The signature was verified in three independent datasets with a total of 658 tumors across multi-platforms...
June 29, 2018: Molecular Oncology
Thatchawan Thanasupawat, Aleksandra Glogowska, Maxwell Burg, Jerry Krcek, Jason Beiko, Marshall Pitz, Guo-Jun Zhang, Sabine Hombach-Klonisch, Thomas Klonisch
The C1Q-TNF related peptide CTRP8 has recently emerged as a novel ligand of the G protein coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8-RXFP1 ligand-receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI-3-kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM...
June 27, 2018: Molecular Oncology
Keefe Murphy, Brendan T Murphy, Susie Boyce, Louise Flynn, Sarah Gilgunn, Colm J O'Rourke, Cathy Rooney, Henning Stöckmann, Anna L Walsh, Stephen Finn, Richard J O'Kennedy, John O'Leary, Stephen R Pennington, Antoinette S Perry, Pauline M Rudd, Radka Saldova, Orla Sheils, Denis C Shields, R William Watson
INTRODUCTION: Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. METHODS: DNA methylation, transcripts, protein, and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multi-block statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO...
June 21, 2018: Molecular Oncology
Sophia Doll, Maximilian C Kriegmair, Alberto Santos, Michael Wierer, Fabian Coscia, Helen Michele Neil, Stefan Porubsky, Philipp E Geyer, Andreas Mund, Philipp Nuhn, Matthias Mann
Recent advances in mass spectrometry (MS)-based technologies are now set to transform translational cancer proteomics from an idea to a practice. Here, we present a robust proteomic workflow for the analysis of clinically relevant human cancer tissues that allows quantitation of thousands of tumor proteins in several hours of measuring time and a total turnaround of a few days. We applied it to a chemorefractory metastatic case of the extremely rare urachal carcinoma. Quantitative comparison of lung metastases and surrounding tissue revealed several significantly upregulated proteins, among them lysine-specific histone demethylase 1 (LSD1/KDM1A)...
June 14, 2018: Molecular Oncology
Jarle Bruun, Anita Sveen, Rita Barros, Peter W Eide, Ina Eilertsen, Matthias Kolberg, Teijo Pellinen, Leonor David, Aud Svindland, Olli Kallioniemi, Marianne G Guren, Arild Nesbakken, Raquel Almeida, Ragnhild A Lothe
We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n=403) or immunohistochemistry (n=642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines...
June 14, 2018: Molecular Oncology
Rola M Saleeb, Mina Farag, Zsuzsanna Lichner, Fadi Brimo, Jenni Bartlett, Georg Bjarnason, Antonio Finelli, Fabio Rontondo, Michelle R Downes, George M Yousef
Papillary renal cell carcinoma (PRCC) is the most common non-clear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2...
June 13, 2018: Molecular Oncology
Seul-Ki Cheon, Hwang-Phill Kim, Ye-Lim Park, Jee-Eun Jang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim
Although MEK blockade has been highlighted as a promising anti-tumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK...
June 13, 2018: Molecular Oncology
Eva Serrano-Candelas, Erola Ainsua-Enrich, Arnau Navinés-Ferrer, Paulo Rodrigues, Alfonso García-Valverde, Sarah Bazzocco, Irati Macaya, Joaquín Arribas, César Serrano, Joan Sayós, Diego Arango, Margarita Martin
Gastrointestinal stromal tumors (GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 (SH3BP2) regulates KIT expression and signaling in human mast cells...
June 9, 2018: Molecular Oncology
Melanie A Blevins, Caiguo Zhang, Lingdi Zhang, Hong Li, Xueni Li, David A Norris, Mingxia Huang, Rui Zhao
The carboxyl-terminal binding proteins (CtBP) are transcriptional corepressors that regulate the expression of multiple epithelial-specific and pro-apoptotic genes. Overexpression of CtBP occurs in many human cancers where they promote the epithelial-to-mesenchymal transition, stem cell-like features, and cell survival, while knockdown of CtBP in tumor cells results in p53-independent apoptosis. CtBPs are recruited to their target genes by binding to a conserved PXDLS peptide motif present in multiple DNA-binding transcription factors...
June 7, 2018: Molecular Oncology
Zhaohui Wang, Nathan J Louras, Alexandre G Lellouch, Shannon G Pratts, Huiping Zhang, Haoyu Wang, Christene A Huang, Curtis L Cetrulo, Joren C Madsen, David H Sachs, Zhirui Wang
Recently, we have developed a diphtheria toxin-based recombinant anti-human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 μg·kg-1 , BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells...
June 5, 2018: Molecular Oncology
Pasano Bojang, Kenneth S Ramos
Long interspersed nuclear element-1 (LINE-1 or L1) reactivation is linked to poor prognosis in non-small-cell lung carcinoma (NSCLC), but the molecular bases of this response remain largely unknown. In this report, we show that challenge of human bronchial epithelial cells (HBECs) with the lung carcinogen, benzo(a)pyrene (BaP), shifted the L1 promoter from a heterochromatic to euchromatic state through disassembly of the nucleosomal and remodeling deacetylase (NuRD) complex. Carcinogen challenge was also associated with partial displacement of constituent proteins from the nuclear to the cytoplasmic compartment...
May 30, 2018: Molecular Oncology
Christianne Hoey, Jessica Ray, Jouhyun Jeon, Xiaoyong Huang, Samira Taeb, Jarkko Ylanko, David W Andrews, Paul C Boutros, Stanley K Liu
Recurrence of high-grade prostate cancer after radiotherapy is a significant clinical problem, resulting in increased morbidity and reduced patient survival. The molecular mechanisms of radiation resistance are being elucidated through the study of microRNA (miR) that negatively regulate gene expression. We performed bioinformatics analyses of The Cancer Genome Atlas (TCGA) dataset to evaluate the association between miR-106a and its putative target lipopolysaccharide-induced TNF-α factor (LITAF) in prostate cancer...
May 30, 2018: Molecular Oncology
Bianca Cioni, Ekaterina Nevedomskaya, Monique H M Melis, Johan van Burgsteden, Suzan Stelloo, Emma Hodel, Daniele Spinozzi, Jeroen de Jong, Henk van der Poel, Jan Paul de Boer, Lodewyk Fa Wessels, Wilbert Zwart, Andries M Bergman
Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including Cancer Associated Fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer progression and stromal cells in the TME also express AR. High-grade tumor and poor clinical outcome is associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against prostate cancer development. However, the mechanism of this relation is not clear...
May 28, 2018: Molecular Oncology
Claudia Göttlich, Meik Kunz, Cornelia Zapp, Sarah L Nietzer, Heike Walles, Thomas Dandekar, Gudrun Dandekar
Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this, we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations, we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: It correctly shows a strong drug response upon gefitinib (Gef) treatment in a cell line harboring an EGFR-activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549)...
May 24, 2018: Molecular Oncology
Christina Therkildsen, Pontus Eriksson, Mattias Höglund, Mats Jönsson, Gottfrid Sjödahl, Mef Nilbert, Fredrik Liedberg
Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UCs of the upper urinary tract and the urinary bladder were identified in the Danish hereditary nonpolyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas...
May 23, 2018: Molecular Oncology
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