Signalling pathways involved in development and cancer, intestinal tumorigenesis, haematological disorders
The majority of tissues in the adult organism contain a population of tissue-specific stem cells. The proper maintenance of adult tissues is controlled by various signalling pathways that regulate the balance between the opposing processes of proliferation and differentiation. Deregulation of these cascades can ultimately lead to cellular transformation and formation of tumours. Cancer is viewed as a genetic disease caused by mutations of proto-oncogenes and tumour suppressors. It is presumed that the first oncogenic mutation provides selective advantage to the prospective cancer cells that multiply and form the initial neoplastic lesion. Moreover, tumours develop over time by acquiring additional alterations that drive tumour progression. The scientific goal of our laboratory is to elucidate the molecular mechanisms influencing the behaviour of normal and transformed cells. At present, the laboratory is focused on two research themes:
Research theme 1 – intestinal stem cells and cancer
Since the fate of intestinal stem cells is determined by the Wnt signalling pathway, our focus is to find genes regulated by Wnt signalling and/or encoding proteins directly involved in the Wnt signal relay. An important result in the current years was identification of the Troy and Nkd1 genes encoding negative regulators of Wnt signalling (Fafilek et al., 2013; Stancikova et al., 2015). In addition, we identified monensin, a carboxylic polyether antibiotic, as a potent and specific inhibitor of the Wnt signalling pathway (Janeckova et al., 2014).
Research theme 2 – haematopoietic stem cells
Myeloproliferative neoplasms (MPN) represent a group of disorders arising due to the genetic defect(s) in haematopoietic pluripotent stem cells. Although the nature of the initiating genetic lesion remains to be elucidated, several studies demonstrated the central importance of genetic alterations in the JAK–STAT signalling pathway in MPN pathogenesis. We are currently focused on characterization of several genetic lesions that might predispose patients to develop MPN and/or contribute to its progression.
The laboratory uses embryonic stem cells to generate novel mouse strains containing so-called conditional alleles of selected genes. In addition, we employ nuclease-based DNA editing to perform direct gene targeting in cells or in the mouse zygote. We also utilize somatic cell reprogramming to generate patient-specific induced pluripotent cells, which might be differentiated to any cell type. Our research is also focused on small molecular inhibitors that could serve as prospective drugs for cancer treatment.
Last change: February 29, 2016