Klinik und Poliklinik
für Innere Medizin II
Klinik und Poliklinik für Innere Medizin II
Direktor: Univ.-Prof. Dr. med. Roland. M. Schmid
direktion.med2@mri.tum.de

Principal Investigator Univ.-Prof. Dr. Rad

Roland Rad is also director of the Institute of Molecular Oncology and Functional Genomics at TUM (www.imo.med.tum.de).

 

We study the molecular processes underlying cancer development and its metastatic spread. Our overarching goal is to better understand the biological basis of cancer in order to advance cancer therapy.


Focus areas are gene discovery, analysis of gene function and signaling in cancer. We develop forward and reverse genetic tools in cells and model organisms and combine genome-scale screening, sequencing, bioinformatics and molecular biology to address basic and translational research questions.

Research background

Our aim

Our research is focused on gene discovery, functional gene annotation and signalling in cancer. We are developing and deploying genetic tools to study molecular tumourigenesis and to identify vulnerabilities that can be exploited for therapeutic targeting. Examples of our approaches are briefly described below.

 

Transposon tools for genome-wide genetic screening in mice

For decades a major bottleneck in cancer research has been the difficulty to identify genetic alterations driving tumourigenesis. Recent advances in next-generation sequencing have tremendously facilitated the search for mutated genes in cancer. However, hundreds and thousands of genes within a single cancer cell are dysregulated by processes other than mutation (e.g. transcriptionally, epigenetically, through upstream targets); and pinpointing the cancer-relevant ones among them still proves to be a major challenge. To address this problem, we have developed unique transposon tools for insertional mutagenesis in mice (Science 2010; Nature Genetics 2015; Nature Genetics 2017).

 

This includes large series of PiggyBac mouse lines for various applications, including constitutive, tissue-specific, dominant or recessive genetic screening. Transposon-based forward genetics allows us to discover cancer-driving molecular processes that are difficult be identified with other approaches to cancer genome analysis. We utilise these systems to uncover mechanisms of tumour evolution, metastatic spread and treatment resistance directly in vivo, in a high-throughput manner, on a genome-wide scale.

 

Our ongoing screens in mice are currently creating comprehensive catalogues of cancer-causing genes, miRNAs and non-coding genomic regions for various solid and haematologic cancers, thus complementing the sequencing-based census of human cancer genes.

 

Mouse models of human cancer

We also develop defined genetically engineered mouse models of cancer for molecular and preclinical studies. A recent example is a mouse model of BrafV600E-induced intestinal tumourigenesis, which uncovered hallmarks of genetic progression as well as targets for therapeutic intervention for this colorectal cancer sub-entity (Cancer Cell 2013).

 

High-throughput functional genomics in mice: large-scale gene targeting and CRISPR/Cas9 somatic multiplex-mutagenesis

One of the biggest challenges in the postgenomic era is to assign biological function to the >20 thousand genes in the human genome. Many aspects of gene function can only be studied at an organismal level, which is however limited by the long-time frames needed to generate and breed genetically engineered model organisms.

 

A focus of our ongoing work is to facilitate reverse genetics in the mouse by developing high-throughput methods to model genetic alterations in vivo. This includes (i) high-throughput conventional gene targeting, which is currently creating a mouse embryonic stem cell resource for several hundred human oncogenes; and (ii) the development of CRISPR/Cas9-based strategies for targeted somatic gene editing in various organs of adult mice.

 

We have, for example, recently demonstrated for the first time that highly multiplexed direct in vivo CRISRP/Cas9 mutagenesis is possible in mice; and we showed proof-of-principle applications of combinatorial somatic genome editing, including cancer induction, genetic screening or chromosome engineering (PNAS 2015; Nature Communications 2016). We have also developed a series of Cas9 knock-in mice (on a C57BL/6 background) supporting conditional Cas9 expression controlled by different promoters from the Rosa26 locus.

 

Next-generation sequencing and bioinformatics

Our research benefits from advances in next-generation sequencing technologies, which we deploy to analyse large-scale genetic screening data (such as CRISRP/Cas9 screens or transposon screens in human cells or mice) or to analyse cancer genomes (e.g. whole-exome sequencing).

 

We are also providing core sequencing and bioinformatics support at the Klinikum rechts der Isar.

Selected Publications

  1. Müller S et al. KRAS gene dosage and evolutionary trajectories define pancreatic cancer phenotypes. Nature 2018 Feb 1;554(7690):62-68.
  2. Wartewig T et al. PD-1 is a haploinsufficient suppressor of T cell lmyphoma-genesis. Nature. 2017 Dec 7;552(7683):121-125

  3. Yuan D et al. Kupffer-cell derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell, 2017 Jun 12;31(6):771-789

  4. de la Rosa J et al. Single-copy Sleeping Beauty transposon identifies new PTEN-cooperating tumor suppressors in prostate cancer. Nature genetics. 2017 May;49(5):730-741

  5. Chapeau E et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo PiggyBac transposon mutagenesis screen in Arf-/- mouse model. Proc Natl Acad Sci USA, 2017, Mar 21;114(12):3151-3156.

  6. Schneider G et al. Oncogenic signalling of cancer drivers: context matters. Nature Reviews Cancer, 2017 Apr;17(4):239-253.

  7. Friedrich M et al. Genome-wide transposon screening and quantitative insertion site sequencing (QiSeq) for cancer gene discovery in mice. Nature Protocols (2017) 12(2):289-309.
  8. Bassani-Sternberg M et al. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nature Communications 2016 21;7:13404.
  9. Stojanovic N, et al. HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. Oncogene. 2016 Oct 10.
  10. Höckendorf U, et al. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell 2016 Jul 11;30(1):75-91.
  11. McKerrell T et al. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. Blood. 2016 Apr 27.
  12. Maresch M et al. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. Nature Communications 2016 Feb 26;7:10770.
  13. Diersch et al. Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cell. Oncogene (2016) Jul 21;35(29):3880-6.
  14. Weber et al. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. PNAS (2015) 112(45):13982-7.
  15. Loregger et al. The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane. Sci Signal (2015) 8(393).
  16. Dietlein F et al. A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell (2015) 162(1):146-59.
  17. Riemer et al. Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity. Oncogene (2015) 34(24):3164-75.
  18. McKerrell et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Reports (2015) 10(8):1239-45.
  19. Rad* et al. A conditional PiggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nature genetics (2015) 47(1):47-56.
  20. Baumann et al. Disruptions of the PRKCD-Fbxo25-Hax-1 axis attenuate the apoptotic response and drive lymphomagenesis. Nature medicine (2014) 20(12):1401-9.
  21. Schönhuber et al. A next-generation dual-recombination system for sequential time and host specific genetic manipulation of pancreatic cancer. Nature medicine (2014) 20(11):1340-7.
  22. de Jong J et al. Chromatin landscapes of retroviral and transposon integration profiles. Plos Genet (2014) 10(4).
  23. de la Rosa J et al. Antagonistic pleiotropy of nuclear lamina integrity on cancer and aging. Nature Communications (2013) 4:2268.
  24. Rad* et al. A genetic progression model of BrafV600E-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell (2013) 24(1):15-29.
  25. Eser et al. Cell autonomous PI3K signalling via Pdk1 is essential for Kras driven pancreatic cancer formation. Cancer Cell (2013) 23(3):406-20.
  26. Klein et al. Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nature Communications (2013) 4:1630.
  27. Lawley et al. Targeted restoration of the intestinal microbiota resolves hypervirulent C. difficile disease and contagiousness. Plos Pathog (2012) 8(10).
  28. Stephens et al. The landscape of cancer genes and mutational processes in breast cancer. Nature (2012) 486(7403):400-4.
  29. Wang et al. Rapid and Efficient Reprogramming of Somatic Cells to iPSCs by Rarg and Lrh-1. PNAS (2011) 108(45):18283-8.
  30. Vassiliou et al. Mutant nucleophosmin and cooperating pathways drive leukaemia initiation and progression in mice. Nature Genetics (2011) 43(5):470-5.
  31. Rad et al. PiggyBac Transposon mutagenesis: A Tool for Cancer Gene Discovery in Mice. Science (2010) 330(6007):1104-7.
  32. Mazur et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic adenocarcinoma. PNAS (2010) 30:13438-43.
  33. Yusa et al. Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nature Methods (2009) 6(5):363-9.
  34. Rad et al. Extra- and intracellular pathogen recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology (2009) 136(7):2247-57.

*corresponding author

Medical theses ⎮ PhD

For inquiries regarding open PhD, MD and postdoc positions please contact by email.

 


Contact

Head: Univ.-Prof. Dr. med. Roland Rad
Institute of Molecular Oncology and Functional Genomics
Klinikum rechts der Isar der TUM
Ismaninger Str. 22 , 81675 Munich, Germany
Tel.: +49 (0) 89 41 40 - 43 74
Fax: +49 (0) 89 41 40 - 79 76

Email: roland.rad@tum.de