Sandra Bondong

Publications (8) View all

• Source

  Available from: Heiner Schäfer

  Article: EMT-associated up-regulation of L1CAM provides insights into L1CAM-mediated integrin signalling and NF-κB activation.

  Helena Kiefel, Sandra Bondong, Marco Pfeifer, Uwe Schirmer, Natalie Erbe-Hoffmann, Heiner Schäfer, Susanne Sebens, Peter Altevogt
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  ABSTRACT: Expression of L1 cell adhesion molecule (L1CAM) is associated with poor prognosis in a variety of human carcinomas including breast, ovarian and pancreatic ductal adenocarcinoma (PDAC). Recently we reported that L1CAM induces sustained nuclear factor kappa B (NF-κB) activation by augmenting the autocrine production of interleukin 1 beta (IL-1β), a process dependent on interaction of L1CAM with integrins. In the present study, we demonstrate that transforming growth factor β1 (TGF-β1) treatment of breast carcinoma (MDA-MB231) and PDAC (BxPc3) cell lines induces an EMT (epithelial to mesenchymal transition)-like phenotype and leads to the expression of L1CAM. In MDA-MB231 cells, up-regulation of L1CAM augmented expression of IL-1β and NF-κB activation, which was reversed by depletion of L1CAM, L1CAM-binding membrane cytoskeleton linker protein ezrin, β1-integrin or focal adhesion kinase (FAK). Over-expression of L1CAM not only induced NF-κB activation but also mediated the phosphorylation of FAK and Src. Phosphorylation was not induced in cells expressing a mutant form of L1CAM (L1-RGE) devoid of the integrin-binding site. FAK- and Src-phosphorylation were inhibited by knock-down of various components of the integrin signalling pathway such as β1- and α5-integrins, integrin-linked kinase (ILK), FAK and the phosphoinositide 3-kinase (PI3K) subunit p110β. In summary, these results reveal that during EMT, L1CAM promotes IL-1β expression through a process dependent on integrin signalling and supports a motile and invasive tumour cell phenotype. We also identify important novel downstream effector molecules of the L1CAM-integrin signalling crosstalk that help to understand the molecular mechanisms underlying L1CAM-promoted tumour progression.
  Carcinogenesis 07/2012; 33(10):1919-29. · 5.70 Impact Factor
• Article: L1CAM: A major driver for tumor cell invasion and motility.

  Helena Kiefel, Sandra Bondong, John Hazin, Johannes Ridinger, Uwe Schirmer, Svenja Riedle, Peter Altevogt
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  ABSTRACT: The L1 cell adhesion molecule (L1CAM) plays a major role in the development of the nervous system and in the malignancy of human tumors. In terms of biological function, L1CAM comes along in two different flavors: (1) a static function as a cell adhesion molecule that acts as a glue between cells; (2) a motility promoting function that drives cell migration during neural development and supports metastasis of human cancers. Important factors that contribute to the switch in the functional mode of L1CAM are: (1) the cleavage from the cell surface by membrane proximal proteolysis and (2) the ability to change binding partners and engage in L1CAM-integrin binding. Recent studies have shown that the cleavage of L1CAM by metalloproteinases and the binding of L1CAM to integrins via its RGD-motif in the sixth Ig-domain activate signaling pathways distinct from the ones elicited by homophilic binding. Here we highlight important features of L1CAM proteolysis and the signaling of L1CAM via integrin engagement. The novel insights into L1CAM downstream signaling and its regulation during tumor progression and epithelial-mesenchymal transition (EMT) will lead to a better understanding of the dualistic role of L1CAM as a cell adhesion and/or motility promoting cell surface molecule.
  Cell adhesion & migration 07/2012; 6(4):374-84. · 1.82 Impact Factor
• Source

  Available from: Dan Cacsire Castillo-Tong

  Article: Fibroblast growth factor receptor 4 gene (FGFR4) 388Arg allele predicts prolonged survival and platinum sensitivity in advanced ovarian cancer.

  Frederik Marmé, Thomas Hielscher, Sarah Hug, Sandra Bondong, Robert Zeillinger, Dan Cacsire Castillo-Tong, Jalid Sehouli, Ioana Braicu, Ignace Vergote, Cadron Isabella, Sven Mahner, Irmgard Ferschke, Joachim Rom, Christof Sohn, Andreas Schneeweiss, Peter Altevogt
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  ABSTRACT: FGFR4 has been shown to play an important role in the etiology and progression of solid tumors. A single nucleotide polymorphism (SNP) within the FGFR4 gene has previously been linked to prognosis and response to chemotherapy in breast cancer and other malignancies. This study evaluates the relevance of this SNP in advanced ovarian cancer. FGFR4-genotype was analyzed in 236 patients recruited as part of the OVCAD project. Genotyping was performed on germ-line DNA using a TaqMan based genotyping assay. Results were correlated with clinicopathological variables and survival. The FGFR4 388Arg genotype was significantly associated with prolonged progression-free and overall survival (univariate: HR 0.68, p = 0.017; HR 0.49, p = 0.005; multivariate: HR 0.69, p = 0.025; HR 0.49, p = 0.006) though the positive prognostic value was restricted to patients without postoperative residual tumor. Indeed, there was a significant interaction between FGFR4 genotype and residual tumor for overall survival. Furthermore, the FGFR4 388Arg genotype significantly correlated with platinum sensitivity in the same subgroup (multivariate OR 3.81 p = 0.004). FGFR4 Arg388Gly genotype is an independent and strong context specific prognostic factor in patients with advanced ovarian cancer and could be used to predict platinum-sensitivity.
  International Journal of Cancer 10/2011; 131(4):E586-91. · 5.44 Impact Factor
• Article: Linking L1CAM-mediated signaling to NF-κB activation.

  Helena Kiefel, Marco Pfeifer, Sandra Bondong, John Hazin, Peter Altevogt
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  ABSTRACT: The cell adhesion molecule L1 (L1CAM) was originally identified as a neural adhesion molecule essential for neurite outgrowth and axon guidance. Many studies have now shown that L1CAM is overexpressed in human carcinomas and associated with poor prognosis. So far, L1CAM-mediated cellular signaling has been largely attributed to an association with growth factor receptors, referred to as L1CAM-'assisted' signaling. New data demonstrate that L1CAM can signal via two additional mechanisms: 'forward' signaling via regulated intramembrane proteolysis and 'reverse' signaling via the activation of the transcription factor nuclear factor (NF)-κB. Taken together, these findings lead to a new understanding of L1CAM downstream signaling that is fundamental for the development of anti-L1CAM antibody-mediated therapeutics in human tumor cells.
  Trends in Molecular Medicine 12/2010; 17(4):178-87. · 10.35 Impact Factor
• Source

  Available from: Dan Cacsire Castillo-Tong

  Article: Prognostic significance of L1CAM in ovarian cancer and its role in constitutive NF-κB activation.

  S Bondong, H Kiefel, T Hielscher, A G Zeimet, R Zeillinger, D Pils, E Schuster, D C Castillo-Tong, I Cadron, I Vergote, I Braicu, J Sehouli, S Mahner, M Fogel, P Altevogt
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  ABSTRACT: Overexpression of L1-cell adhesion molecule (L1CAM) has been observed for various carcinomas and correlates with poor prognosis and late-stage disease. In vitro, L1CAM enhances proliferation, cell migration, adhesion and chemoresistance. We tested L1CAM and interleukin-1 beta (IL-1β) expression in tumor samples and ascitic fluid from ovarian carcinoma patients to examine its role as a prognostic marker. We investigated tumor samples and ascitic fluid from 232 serous ovarian carcinoma patients for L1CAM by enzyme-linked immunosorbent assay. L1CAM expression was correlated with pathoclinical parameters and patients' outcome. IL-1β levels were measured in tumor cell lysates. Ovarian cancer cell lines were analyzed for the contribution of L1CAM to IL-1β production and nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) activation. We observed that L1CAM-expressing tumors show a highly invasive phenotype associated with restricted tumor resectability at primary debulking surgery and increased lymphogenic spread. Soluble L1CAM proved to be a marker for poor progression-free survival and chemoresistance. In ovarian carcinoma cell lines, the specific knock-down of L1CAM reduces IL-1β expression and NF-κB activity. L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1β production and NF-κB activation.
  Annals of Oncology 01/2012; 23(7):1795-802. · 6.43 Impact Factor