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Research

Our research aims on capturing the full compendium of vulnerabilities in human cancer cells by expanding the knowledge of both tumor genotypes and their phenotypic consequences for the successful implementatin of individualized, pathogenesis-oriented cancer therapies. To realize this goal, we are currently pursuing the following reasearch areas and projects:

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Functional characterization of new cancer mutations

We are systematically and comprehensively mapping the function of rare and uncharacterized cancer mutations, which will provide novel mechanistic insights into key cellular pathways and help guide the translation of genomic information into clinical application. Current projects addressing this aim include:

1) Systematic functional analysis of mutations and networks in cancer: It is well established that understanding the genetic alterations in cancer can lead to the development of effective, genotype-directed therapies. Large sequencing efforts have now captured thousands of mutations in many cancer types, thereby revealing that most cancer genes are mutated at low frequencies (under 5%). These rare recurrent mutations are clinically meaningful but not well understood biologically. To address this challenge, we systematically investigate the oncogenic function of uncharacterized rare cancer mutations and their interaction networks, which will improve the interpretation of cancer genomes and help investigators translate genetic information into clinical application. This project is conducted in close collaboration with the groups of Michael Boutros (DKFZ), Ingrid Lohmann (COS, Heidelberg University), Stefan Fröhling (DKFZ and NCT Heidelberg), and Benedikt Brors (DKFZ).

2) Novel mutations in rare cancer types: This project is performed in close collaboration with Stefan Fröhling, coordinator of the NCT/DKTK MASTER program, which aims to implement individualized, pathogenesis-oriented cancer therapies in younger adults with advanced-stage cancer and patients with rare tumors through rapid-turnaround whole-exome/genome and RNA sequencing. Our laboratory mechanistically investigates the oncogenic function of newly discovered recurrent mutations that are identified in this biology-guided stratification program. For example, one project focuses on the functional characterization of mutations in a RAS family member that were identified in a subtype of extragonadal germ cell tumors. In addition, we are currently investigating a novel fusion protein that co-occurs with high expression of an oncogenic receptor tyrosine kinase in a rare subtype of soft-tissue sarcoma.

Identification and characterization of secondary gene dependencies

We are using large scale CRISPR screening and other multi-omics approaches to uncover specific dependencies in different malignancies, such as chordoma, acute myeloid leukemia and mutant KRAS-driven cancer.

1) Systematic interrogation of essential genes in chordoma: Chordomas are rare but devastating malignant tumors with limited therapy options and incomplete knowledge regarding the pathophysiology of the disease. We are using large-scale CRISPR screening in human chordoma cells to identify and characterize genes, signaling proteins, and pathways that are essential for the growth of chordomas and may be exploited for the development of novel therapeutic strategies. This project is performed in close collaboration with Stefan Fröhling (DKFZ and NCT Heidelberg), and is funded by the German Cancer Aid (Deutsche Krebshilfe).

2) Development of Designed Ankyrin Repeat Proteins (DARPins) for targeting TBXT (brachyury) in chordoma: The embryonic transcription factor TBXT is highly expressed in nearly all chordomas, but not normal adult tissues, and is required for chordoma cell survival and proliferation. Thus, TBXT represents in principle an attractive therapeutic target, but transcription factors are difficult to inhibit with small molecules. In close collaboration with Prof. Andreas Plückthun (University of Zurich), we are developing TBXT-targeting DARPins, which is a new class of small-protein therapeutics derived from natural ankyrin repeat proteins that recognize and bind their target proteins by mimicking the functional principle of antibodies. This project is funded by the Wilhelm Sander-Stiftung.

3) Epigenome of oncogenic KRAS (EpiOncoRas): We are systematically investigating the effects of KRAS signaling on the epigenetic landscape in pancreatic and lung cancer. Specifically, we are determining mutant KRAS-induced epigenetic remodeling using omics technologies including ChIP-seq, ATAC-seq, DNA methylation analysis, and RNA-seq in defined cellular models. These studies will substantially improve our understanding of KRAS-mediated tumorigenesis thereby working towards the development of innovative therapies for patients with KRAS-driven cancer. This project is performed in close collaboration with Daniel Lipka (DKFZ), and is funded by the Baden-Württemberg-Stiftung.

4) Vulnerabilities in acute myeloid leukemia (AML): We aim to identify and characterize context-dependent functional vulnerabilities in AML. For example, we identified a novel, non-canonical anti-differentiation function of CDK6 in leukemias driven by MLL rearrangements (Placke et al. Blood 2014), and are now working to understand the mechanistic link between CDK6 inhibition and differentiation induction. Furthermore, we used large-scale RNA interference screening to identify an unexpected dependence of various AML subtypes on the RET receptor tyrosine kinase (Rudat et al. Leukemia 2018). These projects are performed in close collaboration with the laboratory of Stefan Fröhling (DKFZ and NCT Heidelberg).

Study of stem and progenitor cells in the murine lung

This research area focuses on the identification of normal and malignant lung epithelial stem cells and the delineation of regulatory pathways within these cell types in vivo. We developed genetically engineered mouse models that enable us to study the detailed composition of the lung epithelial stem and progenitor cell compartment after cell type-restricted damage using single-cell RNA sequencing. In addition, we are analyzing cancer stem cell function in mutant KRAS-induced lung tumors in mice. This project is part of the Collaborative Research Center SFB873 

Our research is funded by:

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