Division of Applied Functional Genomics

Human cancers are characterized by the acquisition of mutations, such as single-nucleotide variants, small insertions/deletions or copy number alterations. While many of these lesions have been associated with biological characteristics of tumors, the contribution of most mutations to cancer development is unclear. In addition, somatically acquired genetic alterations result in rewiring of intracellular signaling networks during malignant transformation, thereby inducing secondary dependencies on genes that are not directly affected by mutations. Understanding the biological relevance of cancer mutations and their associated secondary dependencies is essential for the successful implementation of individualized cancer therapies. The mission of our laboratory is to find and characterize such specific vulnerabilities in cancer cells that can be exploited for the development of targeted therapies. To achieve this goal, we use a broad spectrum of molecular and cell biological technologies, such as gene manipulation using RNAi, CRISPRi, and CRISPR/Cas9 gene editing on small and large scale in combination with the analysis of diverse in vitro and in vivo phenotypic readouts (e.g. automated microscopy and flow cytometry, protein biochemistry, genetically-engineered mice). We are currently pursuing the following research areas:

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.

Identification and characterization of secondary gene dependencies:
we are using large scale CRISPR screening to uncover secondary dependencies in mesenchymal malignancies (e.g. soft tissue sarcoma and chordoma), we work towards understanding specific vulnerabilities in acute myeloid leukemia, and we characterize epigenetic dependencies in mutant KRAS-driven cancer.

Study of stem and progenitor cells in the murine lung:
we are combining newly developed genetically engineered mouse models and single-cell RNA sequencing to identify normal and malignant lung epithelial stem cells and to delineate the regulatory pathways within these cell types.