Browsing by Author "Ziegler, Annemarie"
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Item Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer(PLoS, 2017) Graumann, Rebecca; Di Capua, Gabriella A.; Oyarzún, Juan; Vásquez, Marcos A.; Liao, Christine; Brañes, Jorge A.; Roa, Iván; Casanello, Paola; Corvalán, Alejandro H.; Owen, Gareth; Delgado, Iris; Uwe, Zangemeister-Wittke; Ziegler, AnnemarieTeneurins are a family of highly conserved pair-rule proteins involved in morphogenesis and development of the central nervous system. Their function in adult tissues and in disease is largely unknown. Recent evidence suggests a role for dysregulated expression of Teneurins in human tumors, but systematic investigations are missing. Here, we investigated Teneurin-2 and Teneurin-4 expression in various cancer cell lines and in ovarian tumor tissues. Teneurin-2 and Teneurin-4 were expressed in most of the breast cancer cell lines tested. Teneurin-4 was also detected in ovarian cancer cell lines, and throughout ovarian tumors and normal ovary tissue. Ovarian tumors with low Teneurin-4 expression showed less differentiated phenotypes and these patients had shorter mean overall survival. Similarly, Teneurin-2 expression correlated with overall survival as well, especially in patients with serous tumors. In the various cell lines, 5-Aza-cytidine-induced changes in DNA methylation did not alter expression of Teneurin-2 and Teneurin-4, despite the existence of predicted CpG islands in both genes. Interestingly, however, we found evidence for the control of Teneurin-2 expression by the oncogenic growth factor FGF8. Furthermore, we identified multiple transcript splicing variants for Teneurin-2 and Teneurin-4, indicating complex gene expression patterns in malignant cells. Finally, downregulation of Teneurin-4 expression using siRNA caused a cell-type dependent increase in proliferation and resistance to cisplatin. Altogether, our data suggest that low Teneurin-4 expression provides a growth advantage to cancer cells and marks an undifferentiated state characterized by increased drug resistance and clinical aggressiveness. We conclude that Teneurin-2 and Teneurin-4 expression levels could be of prognostic value in ovarian cancer.Item Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring(2013) Cerciello, Ferdinando; Choi, Meena; Nicastri, Annalisa; Bausch-Fluck, Damaris; Ziegler, Annemarie; Vitek, Olga; Felley-Bosco, Emanuela; Stahel, Rolf; Aebersold, Ruedi; Wollscheid, BerndBackground: Serum biomarkers can improve diagnosis and treatment of malignant pleural mesothelioma (MPM).However, the evaluation of potential new serum biomarker candidates is hampered by a lack of assay technologies for their clinical evaluation. Here we followed a hypothesis-driven targeted proteomics strategy for the identification and clinical evaluation of MPM candidate biomarkers in serum of patient cohorts. Results: Based on the hypothesis that cell surface exposed glycoproteins are prone to be released from tumor-cells to the circulatory system, we screened the surfaceome of model cell lines for potential MPM candidate biomarkers. Selected Reaction Monitoring (SRM) assay technology allowed for the direct evaluation of the newly identified candidates in serum. Our evaluation of 51 candidate biomarkers in the context of a training and an independent validation set revealed a reproducible glycopeptide signature of MPM in serum which complemented the MPM biomarker mesothelin. Conclusions: Our study shows that SRM assay technology enables the direct clinical evaluation of protein-derived candidate biomarker panels for which clinically reliable ELISA’s currently do not exist.Item Identification of a Rare Germline Heterozygous Deletion Involving the Polycistronic miR-17–92 Cluster in Two First-Degree Relatives from a BRCA 1/2 Negative Chilean Family with Familial Breast Cancer: Possible Functional Implications(2018) de Mayo, Tomás; Ziegler, Annemarie; Morales, Sebastián; Jara, LilianMicro-RNAs (miRNAs) have emerged as novel gene expression regulators. Recent evidence strongly suggests a role for miRNAs in a large variety of cancer-related pathways. Different studies have shown that 18.7 to 37% of all human miRNA genes are clustered. miR-17–92 polycistronic cluster overexpression is associated with human hematolymphoid and solid malignancies including breast cancer (BC). Here, we report the identification of rs770419845, a rare 6 bp deletion located within the polycistronic miR-17–92 cluster, in two first-degree relatives from a Chilean family with familial BC and negative for point mutations in BRCA 1/2 genes. The deletion was identified by Sanger sequencing when 99 BRCA1/2 mutation-negative BC cases with a strong family history were initially screened. In silico analysis predicts that rs770419845 affects the secondary structure and stability of the pre-miR-17–pre-miR-18 region and the entire 17–92 cluster. The deletion was screened in 458 high-risk BRCA1/2-negative Chilean families and 480 controls. rs770419845 was not detected in any control but identified in a single family with two cases of BC and other cancers. Both BC cases, the mother and her daughter, carried the deletion. Based on bioinformatic analyses, the location of the deletion and its low frequency, we presume rs770419845 may be a pathogenic variant. Functional studies are needed to support this hypothesis.Item Impact of arsenic exposure on clinicopathological characteristics of bladder cancer: A comparative study between patients from an arsenic-exposed region and nonexposed reference sites(Elsevier Inc., 2020-02) Fernández, Mario; Valdebenito, Patricio; Delgado, Iris; Segebre, Jorge; Chaparro, Eduardo; Fuentealba, David; Castillo, Martín; Vial, Cecilia; Barroso, Juan; Ziegler, Annemarie; Bustamante, AlbertoBackground: Beyond exposure to arsenic in drinking-water, there is few information about demographic and clinicopathological features of patients with bladder cancer living in arsenic-exposed regions. The aim of the study was to assess the impact of arsenic exposure on clinicopathological characteristics in patients with bladder cancer from a contaminated region compared to those of 2 reference areas. Methods: Data of 285 patients with bladder cancer (83 with arsenic exposure from Antofagasta and 202 controls from 2 different sites in Santiago) were obtained through personal interviews and from review of medical records. Demographic, clinicopathological parameters, and information on relevant environmental risk factors were compared with parametric and nonparametric tests as needed. Multivariable analysis was performed to identify independent predictors for high grade and muscle-invasive disease (T2-4). Results: We found no significant differences between groups regarding age at presentation (66.4 vs. 66.5 and 67.2 years; P = 0.69, for exposed vs. the 2 nonexposed groups, respectively) and female gender (28.9% vs. 29.8% and 26.2%; P = 0.84). Proportion of current smokers was significantly lower in the exposed population (10.7% vs. 38.6% and 26.9%; P < 0.001). There was a significantly higher proportion of locally advanced (10.8 vs. 1.8 and 0.7% T3/4; P = 0.002) and high-grade tumors (79.5% vs. 63.2% and 64.1%; P = 0.001) within arsenic-exposed patients. Arsenic exposure was the only significant predictor for the presence of high-grade tumors (adjusted OR: 5.10; 95%CI: 2.03-12.77) on multivariable analysis. Conclusions: Our study revealed relevant clinical differences in bladder cancer patients with a history of arsenic exposure as compared to nonexposed cases. The more aggressive phenotype associated to arsenic-related bladder cancer should be considered when designing efficient screening strategies for this high-risk population.Item Proteomic surfaceome analysis of mesothelioma(2012) Ziegler, Annemarie; Cerciello, Ferdinando; Bigosch, Colette; Bausch-Fluck, Damaris; Felley-Bosco, Emanuela; Ossola, Reto; Soltermann, Alex; Stahel, Rolf; Wollscheid, BerndIdentification of new markers for malignant pleural mesothelioma (MPM) is a challenging clinical need. Here, we propose a quantitative proteomics primary screen of the cell surface exposed MPM Nglycoproteins, which provides the basis for the development of new protein-based diagnostic assays. Using the antibody-independent mass-spectrometry based cell surface capturing (CSC) technology, we specifically investigated the N-glycosylated surfaceome of MPM towards the identification of proteinmarker candidates discriminatory between MPM and lung adenocarcinoma (ADCA). Relative quantitative CSC analysis of MPM cell line ZL55 in comparison with ADCA cell line Calu-3 revealed a bird’s eye view of their respective surfaceomes.Ina secondary screenoffifteenMPMandsixADCA, weusedhighthroughput low density microarrays (LDAs) to verify specificity and sensitivity of nineteen N-glycoproteins overregulated in the surfaceome of MPM. This proteo-transcriptomic approach revealed thy-1/CD90 (THY1) and teneurin-2 (ODZ2) as protein-marker candidates for the discrimination of MPM from ADCA. Thy1/CD90 was further validated by immunohistochemistry on frozen tissue sections of MPM and ADCA samples. Together, we present a combined proteomic and transcriptomic approach enabling the relative quantitative identification and pre-clinical selection of new MPM marker candidates.Item Teneurin protein family: An emerging role in human tumorigenesis and drug resistance(2012) Ziegler, Annemarie; Corvalán, Alejandro; Roa, Iván; Brañes, Jorge; Wollscheid, BerndUsing a chemoproteomic strategy, we recently demonstrated the expression of teneurin-2, a transmem-brane glycoprotein, in the majority of malignant mesothelioma cell lines. This finding was unexpected since no formally organized evidence existed to implicate teneurins in human malignancy. For this reason, here we provide a comprehensive review on the expression of teneurins in human tumors and cell lines. Current evidence supports the aberrant expression of teneurins in various tumor types, their involvement in cancer-related regulatory networks, and their potential participation in drug resistance. Structural attributes of teneurins could enable the detection of shedded forms in body fluids for clinical applications.Item Teneurins: An Integrative Molecular, Functional, and Biomedical Overview of Their Role in Cancer.(2018) Rebolledo-Jaramillo, Boris; Ziegler, AnnemarieTeneurins are large transmembrane proteins originally identified in Drosophila. Their essential role in development of the central nervous system is conserved throughout species, and evidence supports their involvement in organogenesis of additional tissues. Homophilic and heterophilic interactions between Teneurin paralogues mediate cellular adhesion in crucial processes such as neuronal pathfinding and synaptic organization. At the molecular level, Teneurins are proteolytically processed into distinct subdomains that have been implicated in extracellular and intracellular signaling, and in transcriptional regulation. Phylogenetic studies have shown a high degree of intra- and interspecies conservation of Teneurin genes. Accordingly, the occurrence of genetic variants has been associated with functional and phenotypic alterations in experimental systems, and with some inherited or sporadic conditions. Recently, tumor-related variations in Teneurin gene expression have been associated with patient survival in different cancers. Although these findings were incidental and molecular mechanisms were not addressed, they suggested a potential utility of Teneurin transcript levels as biomarkers for disease prognosis. Mutations and chromosomal alterations affecting Teneurin genes have been found occasionally in tumors, but literature remains scarce. The analysis of open-access molecular and clinical datasets derived from large oncologic cohorts provides an invaluable resource for the identification of additional somatic mutations. However, Teneurin variants have not been classified in terms of pathogenic risk and their phenotypic impact remains unknown. On this basis, is it plausible to hypothesize that Teneurins play a role in carcinogenesis? Does current evidence support a tumor suppressive or rather oncogenic function for these proteins? Here, we comprehensively discuss available literature with integration of molecular evidence retrieved from open-access databases. We show that Teneurins undergo somatic changes comparable to those of well-established cancer genes, and discuss their involvement in cancer-related signaling pathways. Current data strongly suggest a functional contribution of Teneurins to human carcinogenesis.