Division of RNA Biology and Cancer

Prof. Dr. Sven Diederichs

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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. Short non-coding RNAs, the microRNAs, play important roles in gene regulation. The tumor-suppressive or oncogenic role of many microRNAs and their frequent deregulation in tumors allow a first glimpse into the striking role that non-coding RNAs can play in cancer. Novel 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 new and innovative research area of long non-coding RNAs and their role in cancer. 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.


FUTURE OUTLOOK:

As a thriving research area, we analyze long non-coding RNAs (lncRNA) and their role in cancer. After profiling the expression of thousands of lncRNAs in three tumor entities – lung, liver and breast cancer – we elucidate the cellular and molecular function of lncRNAs regulated in cancer. Here, 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 further generate hypotheses on the lncRNA functions, we use bioinformatic guilt-by-association studies. 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.

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 ISIS 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.

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

  • Nachmani D. et al. (2014). RNA binding proteins regulate the expression of the immune activating ligand MICB. Nat Commun, 5: 4186.
  • Hämmerle M. et al. (2013). Post-transcriptional destabilization of the liver-specific long non-coding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). Hepatology, 58(5), 1703–1712.
  • Gutschner T. et al. (2013). The non-coding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res, 73(3), 1180–1189.
  • Gutschner T. et al. (2011). Non-coding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res, 21(11), 1944–1954.
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