GRK 1739 - Research Projects
Project 12Importance of Caveolin-1 for modulating the radiation response in the context of tumor-stroma interactions
PD Dr. rer. nat. Diana Klein
Institut für Zellbiologie (Tumorforschung)
Prof. Dr. Diana Klein
The clinical relevance of the tumor microenvironment in modulating the response of solid tumors to chemotherapy and radiotherapy has been documented. Herein, the membrane protein caveolin-1 (Cav1) came into focus as it is overexpressed or mutated in solid human tumors, e.g. prostate or breast cancer, and regulates several signaling processes and cellular functions with significance for the survival of cancer cells including resistance-promoting interactions with extracellular matrix proteins, tumor angiogenesis and metastasis at advanced tumor stages. However the role of Cav1 for the outcome of radiotherapy is still largely unknown, particularly in the context of tumor stroma interactions. In the proposed project we will explore the role played by Cav1 in the regulation of DNA-damage induction, DNA repair, and cell fate in response to ionizing radiation (IR) in vitro by using genetically modified syngeneic pairs of cancer cells, endothelial cells or fibroblasts with altered Cav1 expression. We will also use genetic approaches to address the role of Cav1 posttranslational modifications and of cancer-associated mutations for the cellular response to ionizing radiation. Moreover we will define signaling pathways that integrate Cav1 into the DNA damage response and cell-fate decisions upon IR. Finally, we will dissect Cav1-driven resistance-promoting tumor stroma interactions in vitro and in vivo in murine models. Our investigations shall foster the development of new therapeutic strategies to target stroma-mediated radiation resistance.
Ketteler J, Panic A, Reis H, Maier P, Herskind C, Yagüe E, Jendrossek V, Klein D. Progression-related loss of stromal Caveolin 1 levels mediates radiation resistance of human prostate xenografts via the apoptosis inhibitor TRIAP1. J Clin Med 2019. In Press.
Zernickel E, Sak A, Riaz A, Klein D, Groneberg M, Stuschke M. Targeting of BRM sensitizes BRG1 mutant lung cancer cell lines to radiotherapy. Mol Cancer Ther. 2018. doi: 10.1158/1535-7163.MCT-18-0067. [Epub ahead of print].
Hlouschek J, Ritter V, Wirsdörfer F, Klein D, Jendrossek V, Matschke J. Targeting of mitochondrial dicarboxylate carrier (SLC25A10) overcomes increased antioxidant capacity and associated radiation resistance induced by chronic-cycling hypoxia. Cancer Letters 2018. Sep 8;439:24-38. doi: 10.1016/j.canlet.2018.09.002.
Ketteler J, Klein D. Caveolin-1, cancer and therapy resistance. Int J Cancer. 2018 Mar 9. doi: 10.1002/ijc.31369.
Wiesemann A, Ketteler J, Slama A, Wirsdörfer F, Hager T, Röck K, Engel D, Fischer J, Clemens Aigner C, Jendrossek V, Klein D. Inhibition of radiation-induced Ccl2 signaling protects lungs from vascular dysfunction and endothelial cell loss. Antioxid Redox Signal. 2018; Accepted.
Al-Refae K, Riffkin H, Wiel G, Handrick R, Klein D, Iliakis G, Jendrossek V. Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity. Sci Rep. 2017;7:42700.
Panic A, Ketteler J, Reis H, Sak S, Herskind C, Maier P, Rübben H, Jendrossek V, Klein D. Progression-related loss of stromal Caveolin 1 levels fosters the growth of human PC3 xenografts and mediates radiation resistance. Sci Rep. 2017;7:41138.
Hess J, Unger K, Orth M, Schötz U, Schüttrumpf L, Zangen V, Gimenez-Aznar I, Michna A, Schneider L, Stamp R, Selmansberger M, Braselmann H, Hieber L, Drexler GA, Kuger S, Klein D, Jendrossek V, Friedl AA, Belka C, Zitzelsberger H, Lauber K. Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. Cancer Lett. 2017;386:87-99.
Klein D, Steens J, Wiesemann A, Schulz FC, Kaschani F, Roeck K, Yamaguchi M, Wirsdörfer F, Kaiser M, Fischer J, Stuschke M, Jendrossek V. Mesenchymal stem cell therapy protects lungs from radiation-induced endothelial cell loss by restoring superoxide dismutase 1 expression. Antioxid Redox Signal. 2016 Aug 29. [Epub ahead of print]
Matschke J, Riffkin H, Klein D, Handrick R, Lüdemann L, Metzen E, Shlomi T, Stuschke M, Jendrossek V. Targeted inhibition of glutamine-dependent glutathione metabolism overcomes death resistance induced by chronic cycling hypoxia. Antioxid Redox Signal. 2016;25(2):89-107.
Schütze A, Vogeley C, Gorges T, Twarock S, Butschan J, Anna Babayan, Klein D, Knauer S, Metzen E, Müller V, Jendrossek V, Pantel K, Milde-Langosch K, Fischer J, Röck K. RHAMM splice variants confer radiosensitivity in human breast cancer cell lines. Oncotarget. 2016;7(16):21428-40.
Klein D, Schmetter A, Imsak R, Wirsdörfer F, Unger K, Jastrow H, Stuschke M, Jendrossek V. Therapeutically applied multipotent stromal cells of mesenchymal nature counteract radiation-induced metastasis by preventing vascular dysfunction and epithelial senescence. Antiox Redox Sign. 2016;24(2):53-69.
Klein D, Schmitz T, Verhelst V, Panic A, Schenck M, Reis H, Drab M, Sak A, Herskind C, Maier P, Jendrosek V. Endothelial Caveolin-1 regulates radiosensitivity of epithelial prostate tumors. Oncogenesis. 2015 18;4:e148.
Klein D, Meissner N, Kleff, Jastrow H, YamaguchiM, Ergün S, Jendrossek V. Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling, Frontiers Oncol. 2014; 4:169.