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Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich
Cancer is a worldwide healthcare problem in humans. Interestingly, companion animals such as dogs and cats also suffer from cancer. Indeed, many of the tumor types that occur in humans are remarkably similar between the three species. Comparative oncology leverages exactly this similarity between tumors of different species to further our understanding of basic cancer biology and identify novel therapeutic approaches. Based on the logic that central mechanisms between different species are conserved rather than less important ones, such a comparison allows the identification of molecular "disease drivers". Furthermore, as certain tumor types that are very rare in humans occur much more frequently in pets, naturally occurring tumors in dogs and cats are considered good models for development of treatment modalities for rare cancers that benefit both human and animal patients.
To analyze specific areas from archival clinical patient material, we have established the isolation and analysis of defined subpopulations of cells from formalin-fixed paraffin-embedded (FFPE) patient tissue by laser-capture microdissection followed by RNA sequencing and LC-MS/MS. Using this approach, we are currently focusing on two key research areas:
Understanding cancer-associated stroma
The non-transformed stromal component of tumors, the so-called cancer-associated stroma (CAS), is central to the development and progression of tumors. However, it is still largely unclear which mechanisms trigger the development of CAS, how CAS affects tumor growth and metastasis, and which structures in CAS represent potential pharmacological targets for cancer therapy in animals and humans. With a focus on breast cancer and melanoma, we aim to identify novel interesting targets in CAS by comparative analysis of patient-derived tissue. Candidates are mechanistically analyzed and validated using different in vitro and in vivo models to identify potential novel pharmacological targets for tumor therapy.
Using this setup, our aim is to answer the following key questions: Which mechanisms lead to the development of CAS? By which molecular mechanisms does CAS influence tumor growth and metastasis? How comparable is CAS between different species? And how can changes in CAS be used as pharmacological targets to treat tumors in animals as well as in humans? This will lead to the identification of key properties of CAS, which in turn allows the development of new biomarkers for tumor progression as well as pharmacological targets for tumor therapy.
Molecular profiling of soft-tissue sarcomas
Soft-tissue sarcomas (STS) are rarely occurring cancers that display locally invasive growth and low to moderate metastatic potential. The low incidence of these rare cancers in humans makes development of novel imaging and treatment strategies almost impossible. Interestingly, STS are much more frequent in dogs and cats and it has been suggested that they could therefore be good models for development of treatment modalities that benefit all three species. However, the lack of detailed molecular characterization of STS in pets impedes their translational potential for pre-clinical trials. Using our powerful technique for analysis of patient tissue, we aim to identify key changes between STS and unaffected peritumoral tissue to define the extent of molecular homology between STS of the three species and identify and validate novel candidates to improve the therapeutic outcome for both human and veterinary patients suffering from STS.
