The role of Hedgehog, Wnt and LGR-receptor induced signalling in stem cells, tumour development and progression
Hedgehog (Hh) and Wnt are embryonically active signalling pathways, also involved in regulation of adult stem cell. Deregulation of Wnt signalling result in increased number of stem cells, altered cell fate as well as tumour formation. In recent year, deregulated Hh signalling has been shown to contribute to tumour formation in several organs, including breast, skin, brain, muscle, lung, pancreas and salivary glands. Amplifications of GLI1, the major Hh effector, have been reported for some types of breast cancer. The molecular consequences of increased GLI1 expression are still not fully understood and Hh induced tumours continue to affect millions of patients every year. In this project we aim to understand the role of Hh and Wnt signalling in breast cancer development and progression.
The transgenic models included in this project are well established and we have long lasting experience working with these models. The tumours developing in the mammary gland are not to hinder for the natural behaviour of the transgenic mice. The included conditional transgenic models ensure spatiotemporal regulation of the transgene expression and tumours will only develop in mice subject to activation of the transgenes. The included protocol for the chemically induced mammary tumours is previously published and optimised to cause minimal stress to the experimental animals. All experimental procedures are internationally accepted and performed by trained personnel to minimise the stress applied on the mice.
Precision medicine depends on the ability to identify each cancer's Achilles heel. Increased knowledge concerning tumour development and progression is of vital importance to improve current care of cancer patients, identify novel cancer drug targets and enable development of new cancer drugs. Breast cancer is the most frequent cancer in women and the therapeutic options for some of the subtypes, e.g. so called triple negative, are very limited. Thus, understanding the molecular mechanisms involved in breast cancer development and progression generates the scientific basis for the development of new therapeutic strategies.
We use transgenic mice, which require a substantial amount of breading to maintain each transgenic line as well as generating experimental mice harbouring several transgenic alleles. Thus, we will use approximately 500 transgenic mice per year (2000 transgenic mice over a period of 4 years).
Organ development and tumour formation depend on complex relationships between different cell populations and signalling molecules and cannot be replaced by any in vitro technique available with today's technology, but is fully depending on an intact living organism. Stem cells, tumour initiating cells and tissue homeostasis cannot be studied in Petri dishes since their existence depends on conditions that are not possible to mimic out side a living organism. We conduct parallel experiments to test the properties of stem cell markers in vitro and we strive to replace the in vivo experiments with in vitro experiment when suitable in vitro alternatives are available. Furthermore, we follow relevant literature, participate in meetings and discussions aiming at refining our experimental procedures and reducing the number of animals required to obtain valid experimental data.
The transgenic models included in this project are well established and we have long lasting experience working with these models. The tumours developing in the mammary gland are not to hinder for the natural behaviour of the transgenic mice. The included conditional transgenic models ensure spatiotemporal regulation of the transgene expression and tumours will only develop in mice subject to activation of the transgenes. The included protocol for the chemically induced mammary tumours is previously published and optimised to cause minimal stress to the experimental animals. All experimental procedures are internationally accepted and performed by trained personnel to minimise the stress applied on the mice.
Precision medicine depends on the ability to identify each cancer's Achilles heel. Increased knowledge concerning tumour development and progression is of vital importance to improve current care of cancer patients, identify novel cancer drug targets and enable development of new cancer drugs. Breast cancer is the most frequent cancer in women and the therapeutic options for some of the subtypes, e.g. so called triple negative, are very limited. Thus, understanding the molecular mechanisms involved in breast cancer development and progression generates the scientific basis for the development of new therapeutic strategies.
We use transgenic mice, which require a substantial amount of breading to maintain each transgenic line as well as generating experimental mice harbouring several transgenic alleles. Thus, we will use approximately 500 transgenic mice per year (2000 transgenic mice over a period of 4 years).
Organ development and tumour formation depend on complex relationships between different cell populations and signalling molecules and cannot be replaced by any in vitro technique available with today's technology, but is fully depending on an intact living organism. Stem cells, tumour initiating cells and tissue homeostasis cannot be studied in Petri dishes since their existence depends on conditions that are not possible to mimic out side a living organism. We conduct parallel experiments to test the properties of stem cell markers in vitro and we strive to replace the in vivo experiments with in vitro experiment when suitable in vitro alternatives are available. Furthermore, we follow relevant literature, participate in meetings and discussions aiming at refining our experimental procedures and reducing the number of animals required to obtain valid experimental data.