Dissecting the role of tumor cell heterogeneity in Pancreatic Neuroendocrine Tumor progression
Group Marinoni, Perren, Sadowski Cancer is a dynamic disease; genetic and epigenetic alterations drive intra-tumoral cell heterogeneity, resulting in the selection of aggressive cell populations capable of driving progression and ultimately metastasis. Pancreatic neuroendocrine tumours (PanNETs) are tumours that arise from the islets of Langerhans. They exhibit intra-tumoral cell heterogeneity, but it is unclear how this evolves during tumour development and how it contributes to progression. Our previous data suggest that epigenetic changes are the major drivers of progression and cell heterogeneity in PanNETs. By integrating epigenetic and transcriptomic profiles, we found that cell dedifferentiation and metabolic changes characterise the progression from small PanNETs to more advanced ones. We are currently investigating the evolution of intra-tumoral heterogeneity of PanNETs through space and time. Specific cell subpopulations identified as driving progression could then be targeted to stop metastasis formation. The identification of targetable pathways that impair metastasis formation will provide a rationale for new treatments.
Oncogenic signaling via receptor tyrosine kinases in crosstalk with DNA damage repair
Gruppe Medova Tyrosine kinase receptors activate a wide range of different cellular signaling pathways. Physiologically, intact signaling via the MET receptor is indispensable in embryonic development and tissue homeostasis. At the same time, MET dysregulation promotes features clearly associated with tumor growth and progression such as uncontrolled proliferation, angiogenesis, local invasion, and systemic dissemination. Accumulating data suggest that MET signaling may also protect tumor cells from DNA damage, hence relating its aberrant activity to resistance to DNA-damaging agents routinely used in cancer treatment. We have identified a previously unreported phosphorylation site on MET, which can be recognized by DNA damage master kinases and is involved not only in cellular responses towards DNA damage, but also in metastatic processes, cancer cell migration, and anchorage-independent growth. This project aims at dissecting the nature, function, and regulation of this phosphorylation site in oncogenic signaling of the receptor.