Oncogenic Signal Transduction Pathways as Targets for Personalized Tumor Therapy

Cancer research and develpmental biology address similar questions: How do genes control cell proliferation, how is the formation of three-dimensional structures in organs achieved, how are superfluous cells eliminated by the organism, and how can specific molecular alterations modify the behavior of individual cells? The same signal transduction pathways that control the development of multicellular organisms and the proliferation of stem cells are frequently mutated and thereby deregulated in human cancers. Therefore, research on simple animal model organisms such as C. elegans (roundworm) or Drosophila melanogaster (fruit fly) can significantly contribute to the understanding of genetic and biochemical events leading to cancer formation in humans. Research in mammalian models can extend the elucidated concepts and provide further insights into the role of the host including the complex tumor microenvironment.

Tumor cell invasion is a prominent example to illustrate the integrative approach taken by this URPP. Most cancer-related deaths are not caused by the primary tumor but rather by metastases that have spread to distant sites. An initiating event in the conversion of primary tumor cells into metastatic cells is an epithelial-to-mesenchymal transition that generates a population of invasive cells that are capable of crossing the basal lamina delineating compartment boundaries and entering blood or lymphatic vessels, ultimately leading to the dissemination of malignant cells. The genetic and epigenetic factors underlying this “invasive switch” in individual tumor cells are therefore under intense investigation. Studies in developmental biology demonstrated that cell invasion also occurs in a strictly regulated fashion during normal development, e.g. in neural crest stem cells. The molecular pathways activating the developmental cell invasion program are being identified and studied in animal model organisms where cell invasion can be easily observed. Importantly, recent evidence indicates that the very same signaling pathways activating cell invasion during normal development, when deregulated in tumors, such as in melanoma, lead to the formation of invasive cancer cells.

By bringing together researchers studying oncogenic signaling pathways in the context of normal animal development with clinical scientists studying the related pathways in human tumor cells, this URPP will generate vital synergies for both clinical and basic research. Rather than focusing on individual signaling pathways to understand the complex cellular responses to extrinsic signals, we will characterize the entire signaling networks formed by the crosstalk of individual pathways. This will allow us, for example, to investigate compensatory mechanisms underlying tumor escape to a previously efficacious drug and predict the outcome of alternative or combined therapeutic interventions at the molecular level; this is key for the development of next generation (personalized) anti-cancer strategies. The members of this network will use a variety of methods, depending on the model system investigated, including but not limited to siRNA screens and pharmacological studies of specific inhibitors in cultured tumor cells, forward genetic screens in model organisms, genetic association studies in humans, systems genetics in animals, and deep sequencing in well-defined human tumor samples linked to clinical outcome data.

Our specific aims are:

1. Identification of molecular pathways relevant to tumor cell biology with a special emphasis on developmental biology, stem cell biology and tumor-host interactions (tumor angiogenesis, plasticity, invasion and metastasis).

2. Validation of the implicated signaling pathways using cultured primary tumor cells best suited for therapeutic intervention.

3. Initial development of novel therapeutic approaches, including innovative tools for drug delivery, advanced antibody technology and novel, innovative small molecule inhibitors.