Finding and understanding cancer dependencies using functional genetics

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The genetic complexity, heterogeneity and plasticity of human cancers pose daunting challenges for the development of effective targeted therapies. Functional-genetic tools such as CRISPR/Cas9 advanced RNAi and degron technologies fundamentally change the way we can approach this problem. Our lab develops and employs these tools in genetically engineered mouse models, which provide a unique system to identify, validate and study cancer dependencies in a physiologic microenvironment. One major focus is the functional exploration of drivers and master regulators of aberrant cell-fate programs in leukemia, which we decipher using multiplexed CRISPR and shRNAmir screens and funtionally characterize through combining RNAi- and degron-based loss-of-function tools with innovative profiling techniques such as SLAM-seq. Another major goal is the identification of synergistic target interactions to guide the development of rational combinatorial therapies, which we are exploring in AML and PDAC models using complementary CRISPR- and shRNAmir-based screens. Most recently, we have adapted focused CRISPR screens for identifying candidate targets in tumor-associated CD8 T and NK cells. Collectively, our vision is to further develop and employ innovative functional-genetic tools to systematically identify, rigorously validate and mechanistically study candidate therapeutic targets prior to drug development.

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Biosketch

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Johannes Zuber is a group leader at the Research Institute of Molecular Pathology (IMP) in Vienna. He studied medicine and received a doctorate in molecular cancer research at the Charité Medical School in Berlin. Following a four-year clinical residency in hematology and oncology, he joined Scott Lowe's lab at Cold Spring Harbor Laboratory as a postdoc, where he later was appointed as Clinical Research Fellow. In 2011, he founded his own lab the IMP, where he develops and employs functional-genetic approaches for identifying and probing therapeutic targets in leukemia and other cancers. He received an ERC Starting Grant in 2015, has been selected as an EMBO Young Investigator (YIP), and has been awarded with the German Cancer Prize in 2016. In 2017, he has been appointed as an Adjunct Professor at the Medical University of Vienna.

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