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Division of RNA Biology and Cancer

Prof. Dr. Sven Diederichs

The Argonautes - Per aspera ad astra
© dkfz.de

A large fraction of the human genome is transcribed into RNA (more than 70%), while only 2% are protein-encoding. These recent insights into RNA biology induced a paradigm shift toward the recognition of RNAs as functionally important molecules – beyond serving as messengers for protein-encoding genes. Non-protein-coding RNAs execute important functions in the cell. Long non-coding RNAs (ncRNA, lncRNA, lincRNA) fulfill important functions ranging from epigenetic gene regulation to scaffolding functions in the cytoplasm. Taken together, the human cell contains many more RNAs than previously anticipated and many of them might just be awaiting their discovery as functionally important molecules. Since cancer is – in most cases – a disease of the genome that is caused by the deregulation of oncogenes and tumor suppressor genes, we are convinced that studying all parts of the human genome is important in tumor biology, as opposed to restricting ourselves to studying the 2% of protein-coding information.

Our research focuses on the innovative research area of RNA-protein complexes and their role in cancer. Since most RNAs function in ribonucleoprotein complexes, we have developed the concept of RNA dependence (Mol Cell 2019, Nat Protoc 2020) and screened proteome-wide for RNA-dependent protein complexes. This comprehensive dataset allows the identification of entirely novel and unexpected functions of RNAs at the molecular level. We further pursue these RNA-dependent protein complexes with an emphasis on cancer-related pathways and phenotypes.

For the study of long non-coding RNAs, we focus on three tumor entities – lung, liver and breast cancer (e.g. Hepatology 2018, Nat Commun 2020). We elucidate the expression patterns, regulatory mechanisms and cellular and molecular functions of lncRNAs relevant to cancer. The fascination, as well as the major challenge in lncRNA research is driven by the fact that each lncRNA can have a different function and a different mechanism, so that many important discoveries and insights into the molecular mechanisms underlying tumorigenesis can be expected from this field. In this thriving research area, we use innovative techniques like Genome Editing to silence lncRNAs in cancer cells and RNA Affinity Purification to identify the interactomes of cancer-associated lncRNAs. To accelerate our discoveries of novel lncRNAs in cancer, we have developed an siRNA library specifically targeting 638 cancer-associated lncRNAs identified in our screen and allowing for their rapid functional characterization. Additionally, we employ an sgRNA library for CRISPRi-mediated screening covering 2098 lung cancer-associated genes with 42000 guide RNAs.

One example nicely illustrates our research approach: We identified the lncRNA MALAT1 (Metastasis-Associated in Lung Adenocarcinoma Transcript 1) as a biomarker associated with a poor prognosis and the development of distant metastasis in lung cancer (Oncogene 2003). We then developed a novel approach to quantitatively silence this lncRNA in lung cancer cells by genome editing (Genome Res 2011). This loss-of-function revealed that MALAT1 was essential for cell migration and metastasis in a xenograft mouse model. Joining forces with Ionis Pharmaceuticals, we developed an inhibitor for MALAT1, an Antisense Oligonucleotide (ASO), which effectively reduced MALAT1 in the mouse model and suppressed lung cancer metastasis (Cancer Res 2013). At the molecular level, we identified MALAT1 as an epigenetic regulator inducing a signature of metastasis-associated genes. In summary, MALAT1 can serve as a biomarker and is an essential player and promising therapeutic target for metastasis prevention in lung cancer.

Most recently, we have delved into the novel research area of "non-canonical mutations" in cancer (EMBO Mol Med 2016, Nat Commun 2019, Nat Cell Biol 2020). These include mutations in the non-coding areas of the genome, but also mutation types not previously studied in cancer like synonymous mutations (Nat Commun 2019) or nonstop extension mutations (Nat Cell Biol 2020). For both of these classes, we were able to discover highly relevant impacts on important oncogenes like KRAS or tumor suppressor genes like SMAD4.

Contact

Prof. Dr. Sven Diederichs
RNA Biology and Cancer (B150)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 4380

Selected Publications

  • Dhamija S.*, et al. (2020). A Pan-Cancer Analysis reveals Nonstop Extension Mutations causing SMAD4 Tumor Suppressor Degradation. Nature Cell Biology epub
  • Gandhi M., et al. (2020). The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer. Nature Communications 11: 3214
  • Sharma Y.*, et al. (2019). A pan-cancer analysis of synonymous mutations. Nature Communications 10: 2569
  • Caudron-Herger M., et al. (2019). R-DeeP: Proteome-wide and Quantitative Identification of RNA-dependent Proteins by Density Gradient Ultracentrifugation. Molecular Cell 75: 184-199
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