Division of Cancer Research in Thoracic Surgery (Prof. Dr. Sven Diederichs)
Non-canonical Mutations in Cancer: Nonstop, Synonymous and beyond...
It is widely accepted that cancer - in many cases - is a genetic disease caused by mutations that activate oncogenes and inhibit tumor suppressor genes. However, cancer genetics has mostly focused on "canonical" mutations known to alter the protein like missense or nonsense mutations, deletions or amplifications.
We have found that also other types of mutations, which have so far been overlooked, can have a significant impact on cancer genes - like nonstop extension mutations or synonymous mutations. While they may be less recurrent and more difficult to study, they nonetheless need to be functionally characterized and explored for their impact on patient stratification, where they are currently mostly disregarded.
(EMBO Mol Med 2016, Nat Commun 2019, Nat Cell Biol 2020)
Molecular Biology of Lung Cancer & Metastasis
Lung cancer is the leading cause of cancer-associated death world-wide. While its etiology based on smoking is well established, the molecular changes leading to this malignant disease are often not understood. This lack of molecular insight into tumorigenesis also frequently precludes the development of innovative and highly specific new drugs.
Metastasis - the development of new tumor nodules in distant organs - is the most frequent cause of death of all solid tumor entities. One of the distant sites most often affected by metastasis is the lung.
In our Division for Cancer Research in the Department of Thoracic Surgery, we hence investigate the mechanisms and networks, the regulation and function of the molecules involved in these essential processes to understand the processes and pathways leading to the development of lung cancer and metastasis to enable the future development of novel therapy approaches based on these mechanisms.
(Cancer Res 2013, Nucleic Acids Res 2017, Cancers 2020)
A particular emphasis of our research lies on the Molecular Biology of RNA and its associated molecules.
Recent insights into RNA biology induced a paradigm shift towards the recognition of RNAs as functionally important molecules - beyond serving as messengers for protein-encoding genes. A large fraction of the human genome is transcribed into RNA (more than 70%), while only 2% are protein-encoding. Non-protein-coding RNAs execute important functions in the cell. Very 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 of the striking role that non-coding RNAs could play in cancer. Novel long non-coding RNAs (ncRNA, lncRNA, lincRNA) fulfill important functions in epigenetic regulation, chromatin remodeling or splicing. Taken together, the human cell contains many more RNAs than previously anticipated and many of them might just await their discovery as functionally important molecules in cancer.
Our research focuses on long non-coding RNAs (lncRNAs) and their role in cancer. Based on expression profiling using microarrays as well as deep RNA sequencing of the whole transcriptome, we elucidate the cellular and molecular functions of differentially regulated ncRNAs in cancer using innovative techniques like the CRISPR/Cas9 system, in vivo RNA Affinity Purification and our own customized siRNA and CRISPR libraries targeting specifically lung cancer-associated lncRNAs. Our RNAi screens have uncovered numerous lncRNAs controlling several hallmarks of cancer including cancer cell viability, mitosis and migration.
Moreover, we are interested in mutations outside of the coding region that play a role in the development or progression of lung cancer and other solid tumors.
(Nature 2015, Mol Cell 2019, Nat Protoc 2020, Nat Commun 2020)
Future Projects and Goals:
- Regulation, function, mechanism and interactome of long non-coding RNAs and RNA binding proteins in lung cancer and metastasis
- Impact of novel mutation types in solid tumors
- Molecular determinants of epigenetic drug sensitivity in lung adenocarcinoma