Hedgehog signalling, tissue stem cells and cancer development - Rune Toftgård
Inappropriate reactivation of developmental signalling pathways such as the Hedgehog (Hh) pathway is a common event during cancer development.
Mutational inactivation or activation of core components of the Hh-pathway underlies cell autonomous activation in basal cell carcinoma of the skin (BCC) and in medulloblastoma. In other tumour types such as pancreatic cancer and breast cancer additional activation mechanisms are present.
A major focus of our research is to understand the details of Hh signalling at the genetic, molecular and structural level with emphasis on the key intracellular SUFU and GLI components. Secondly, to understand how aberrant activation of this pathway can drive cancer development in skin, mammary gland and pancreas combining studies of genetically modified preclinical models and of human tissues. Thirdly, to devise new methods aimed at pharmacological inhibition of the Hh signalling pathway at the level of the GLI transcriptional effectors building on our detailed biological and molecular studies of the pathway.
To understand cancer biology and how to best eradicate tumour cells we must know the biology of normal tissues including the nature of tissue stem and progenitor cells, their interconversions and their ability to serve as cancer cell of origin. With this aim we investigate the presence and functional properties of tissue stem cells marked by expression of Lgr5 and Lgr6 in human and murine skin and mammary gland.
Picture of a part of a human hair follicle illustrating expression of the tissue stem cell markers SOX9 (red) and LGR5 (green) in the outer root sheath keratinocytes. Positive staining for LGR5 is also seen in sebocytes. Nuclei are counterstained in blue.