Project 10 Role of stromal hyaluronan in radiation sensitivity

 

Principal Investigator

Prof. Dr. rer. nat. Jens W. Fischer

Summary

The laboratory of Prof. Fischer analyzes the functions of hyaluronan (HA) synthase isoenzymes and HA receptors, as well as novel regulatory pathways in a variety of tumor models and mesenchymal cells (fibroblasts and smooth muscle cells) where Dr. Röck adds specific expertise in tumor biology. Aim is to identify new targets of therapy by analyzing the functions of the extracellular matrix (ECM) in tumor pathophysiology. Along these lines the project integrated in the present RTG focuses on esophageal cancer (eSCC). eSCC) is the eighth-most common cancer globally with 456,000 new cases each year. Despite surgery or radiochemotherapy (RCT) the five-year survival rate remains around 15% indicating the need for new therapy regimens. Hyaluronan (HA), a major carbohydrate component of the cellular microenvironment, acts through multiple signaling pathways to promote phenotypic hallmarks of malignant cells such as resistance to cell death, proliferation and migration. Own previous work has demonstrated that irradiated fibroblasts enhance eSCC cell sensitivity to IR in a HA dependent manner in vitro. Reduction of stromal HA after irradiation led to formation of tunneling nanotubes, which shuttle proteins and cell organelles from the fibroblasts into tumor cells. Based on these results we will clarify whether the identified fibroblast proteins contribute to increased tumor cell death in cocultures of irradiated fibroblasts and eSCC cells. Specifically the function and role of the detected fibroblast proteins will be investigated in vitro and in xenograft models. The experiments will also reveal whether the shuttled protein and/or HA-synthesis and HA-signaling may be considered as new therapeutic targets.

 

1.       Klein D, Steens J, Wiesemann A, Kaschani F, Röck K, Wirsdörfer F, Kaiser M, Fischer JW, 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 (in press)

2.       Röck K, Joosse SA, Müller J, Heinisch N, Fuchs N, Meusch M, Zipper P, Reifenberger J, Pantel K, Fischer JW. Chronic UVB-irradiation actuates perpetuated dermal matrix remodeling in female mice: Protective role of estrogen. Sci Rep. 2016 Jul 27;6:30482. doi: 10.1038/srep30482.

3.       Schütze A, Vogeley C, Gorges T, Twarock S, Butschan J, Babayan A, Klein D, Knauer SK, Metzen E, Müller V, Jendrossek V, Pantel K, Milde-Langosch K, Fischer JW, Röck K. RHAMM splice variants confer radiosensitivity in human breast cancer cell lines. Oncotarget. 2016 Apr 19;7(16):21428-40. doi: 10.18632/oncotarget.7258.

4.       Kretschmer I, Freudenberger T, Twarock S, Fischer JW. Synergistic effect of targeting the epidermal growth factor receptor and hyaluronan synthesis in oesophageal squamous cell carcinoma cells. Br J Pharmacol 2015; doi: 10.1111/bph.13240 [Epub ahead of print].

5.       Röck K, Tigges J, Sass S, Schutze A, Florea AM, Fender AC, Theis FJ, Krutmann J, Boege F, Fritsche E, Reifenberger G, Fischer JW. miR-23a-3p causes cellular senescence by targeting hyaluronan synthase 2: possible implication for skin aging. J Invest Dermatol 2015;135(2):369-77.

6.       Niedworok C, Kretschmer I, Röck K, Vom Dorp F, Szarvas T, Hess J, Freudenberger T, Melchior-Becker A, Rubben H, Fischer JW. The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. PLoS One 2013;8(9):e75681. Appendix I 65

7.       Niedworok C, Röck K, Kretschmer I, Freudenberger T, Nagy N, Szarvas T, Vom Dorp F, Reis H, Rubben H, Fischer JW. Inhibitory role of the small leucine-rich proteoglycan biglycan in bladder cancer. PLoS One 2013;8(11):e80084.

8.       Lichtenberger BM, Gerber PA, Holcmann M, Buhren BA, Amberg N, Smolle V, Schrumpf H, Boelke E, Ansari P, Mackenzie C, Wollenberg A, Kislat A, Fischer JW, Röck K, Harder J, Schroder JM, Homey B, Sibilia M. Epidermal EGFR controls cutaneous host defense and prevents inflammation. Sci Transl Med 2013;5(199):199ra11.

9.       Röck K, Meusch M, Fuchs N, Tigges J, Zipper P, Fritsche E, Krutmann J, Homey B, Reifenberger J, Fischer JW. Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes. J Biol Chem 2012;287(24):20056-69.

10.    Röck K, Grandoch M, Majora M, Krutmann J, Fischer JW. Collagen fragments inhibit hyaluronan synthesis in skin fibroblasts in response to ultraviolet B (UVB): new insights into mechanisms of matrix remodeling. J Biol Chem 2011;286(20):18268-76.

11.    Röck K, Fischer K, Fischer JW. Hyaluronan used for intradermal injections is incorporated into the pericellular matrix and promotes proliferation in human skin fibroblasts in vitro. Dermatology. 2010;221(3):219-28. doi: 10.1159/000318905.

12.    Twarock S, Röck K, Sarbia M, Weber AA, Jänicke RU, Fischer JW. Synthesis of hyaluronan in oesophageal cancer cells is uncoupled from the prostaglandin-cAMP pathway. Br J Pharmacol. 2009 May;157(2):234-43. doi: 10.1111/j.1476-5381.2009.00138.x. Epub 2009 Mar 26.