Division of Applied Functional Genomics

All 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 complex quantitative and qualitative changes of intracellular signaling networks during malignant transformation, thereby inducing specific dependencies on genes that are not directly affected by mutations. 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 RNA interference or CRISPR/Cas9-mediated genome editing on small and large scale in combination with the analysis of diverse in vitro and in vivo phenotypic readouts.

We are particularly focusing on the identification and characterization of genotype-selective functional vulnerabilities in acute myeloid leukemia (AML) and solid-organ malignancies harboring oncogenic KRAS mutations. In addition, we are using lung tumor mouse models and proteomic approaches to delineate the function of STK33, an uncharacterized serine/threonine kinase that is essential for the survival of mutant KRAS-dependent cancer cells. We also developed genetically engineered mouse models for the Identification of normal and malignant lung epithelial stem cells and delineation of regulatory pathways within these cell types through single-cell RNA sequencing. Finally, we recently initiated a collaborative scientific program centered on the systematic functional characterization of rare mutations in cancer genomes, complementing translationally oriented cancer genome sequencing efforts. This approach will allow the systematic discrimination between pathogenetically relevant driver mutations and biologically neutral passenger alterations.

FUTURE OUTLOOK
We will continue to work towards a better understanding of specific functional dependencies in AML and, in particular, KRAS mutant cancers. The identification of new lung stem and progenitor cell types will allow us to investigate their role in mutant KRAS-induced lung tumor formation using newly generated mouse models. Finally, we aim to systematically and comprehensively map 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.