Summary

Many cancers are comprised of heterogeneous tumor cells with various differentiation and specialization, analogous to the organization of normal tissues. The subclonal diversity within individual tumors – caused by accumulating mutational patterns and epigenetic manifestations (clonal evolution model) as well as various stages in differentiation (stem cell model) – hamper current therapies, and contribute to clonal resistance and selection. Targeting tumor-initiating stem cells that may escape standard therapy and lead to the relapse of the disease, must be achieved to eliminate them for long-term remission. These principles largely apply to solid tumors as well as hematologic malignancies.
We aim to dissect tumor cell heterogeneity and individual tumor cell behavior to find molecular targets for the long-lasting elimination of all tumor cells. The emergence and composition of initial events leading to the formation of premalignant cells that acquire clonal dominance, and the events resulting in disease progression, clonal evolution and tumor cell specification are investigated. Understanding the sequential order of oncogenic mechanisms leading to full-blown disease will reveal distinct vulnerables to target malignant cells at various stages of the disease.
We focus our research on basic mechanisms that control stem cell fate decisions that need to be strictly balanced for tissue regeneration and for emergency situations, and are often dysregulated in cancer. We utilize various organ stem cell systems (hematopoietic cells, colon) from mice and humans to unravel molecular and functional clues how these decisions are integrated in normal stem cell biology and how malignant stem cells can be targeted for innovative cancer treatment.
Therefore we apply various single cell technologies including time-lapse microscopy-based cell tracking, multi-parameter flow cytometry, single cell RNA sequencing and clonal barcoding. Developing concepts of oncogenic mechanisms in preclinical mouse models and translating these principles to patient-derived tumor samples will inform molecular and functional control of tumor initiation, progression and treatment resistance.