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Cell Plasticity and Epigenetic Remodeling

Helmholtz University Junior Research Group Cell Plasticity and Epigenetic Remodeling

Dr. Darjus Tschaharganeh

Immunofluorescence image of the small intestine of an shRNA-transgenic mouse for studying tumor heterogeneity. The different fluorescence dyes (red, green, blue) indicate three different shRNAs.
© dkfz.de

Facilitated by advances in genome sequencing technologies during the past 30 years researchers are now able to obtain a comprehensive overview of genomic alterations in almost every cancer type. These data revealed a number of frequent alterations and mutational patterns in different cancer types, pinpointing to potential candidate “driver” genes for particular diseases. Although this information is very valuable it is purely descriptive. Therefore, subsequent functional studies in appropriate model systems are necessary to assign phenotypical consequences to these “drivers”, which not only help to understand cancer biology but also facilitate development of new therapeutic targets for personalized cancer medicine. Our laboratory has strong expertise in applying functional genomic tools, such as RNA-interference and CRISPR/Cas9, to create innovative and powerful mouse models of cancer. We use these tools to generate genetically defined tumors, which closely resemble alterations found in human cancer samples, thereby probing the function of specific genetic events on tumor development. Subsequently we utilize the models we create for investigating specific vulnerabilities created by these defined genetic events by employing state-of-the-art high-throughput screening technology in vitro and in vivo.

Our future research will continue to characterize cancer genomes using the functional genomics approaches outlined above. In particular we are interested in epigenetic modifications as well as genes responsible for mediating epigenetic remodeling. This group of genes is frequently altered in human cancer but remains poorly characterized. We aim to investigate their relevance in cancer development and to define their suitability to represent specific vulnerabilities for cancer therapy. In fact a variety of epigenetic drugs are currently under development and show promising success. Furthermore, our lab will develop technologies to interrogate epigenomes in vitro and in vivo to facilitate the study of epigenetic processes. More recently we are interested to adjust our mouse model technology for studying the impact of the immune system in tumorigenesis. Here our research will focus on constructing synthetic genetic circuits for visualizing and interrogating intercellular communication of tumor cells and immune cells as well as defining determinants for improving immunotherapeutic response.

Contact

Dr. Darjus Tschaharganeh
Cell Plasticity and Epigenetic Remodeling (F190)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 5634555

Selected Publications

  • Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW. (2014). p53 dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell., 158(3):579-92.
  • Breinig M, Schweitzer AY, Herianto AM, Revia S, Schaefer L, Wendler L, Cobos Galvez A, Tschaharganeh DF. Multiplexed orthogonal genome editing and transcriptional activation by Cas12a. Nat Methods. 2018 Dec 17
  • Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Fan B, Ribback S, Jiang L, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K. (2013) Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology, 4(7):1530-1542.e12.
  • Zafra MP, Schatoff EM, Katti A, Foronda M, Breinig M, Schweitzer AY, Simon A, Han T, Goswami S, Montgomery E, Thibado J, Kastenhuber ER, Sánchez-Rivera FJ, Shi J, Vakoc CR, Lowe SW, Tschaharganeh DF, Dow LE. Optimized base editors enable efficient editing in cells, organoids and mice. Nat Biotechnol. 2018 Oct;36(9):888-893.
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