MAMMAHOGLGR
Understanding Hedgehog signalling in breast cancer and mammary gland stem cells using tissue specific expression of Gli1 the main effector of the Hedgehog pathway
| Coordinatore | KAROLINSKA INSTITUTET
Organization address
address: Nobels Vag 5 contact info |
| Nazionalità Coordinatore | Sweden [SE] |
| Totale costo | 179˙223 € |
| EC contributo | 179˙223 € |
| Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | FP7-PEOPLE-IEF-2008 |
| Funding Scheme | MC-IEF |
| Anno di inizio | 2009 |
| Periodo (anno-mese-giorno) | 2009-07-01 - 2011-06-30 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
KAROLINSKA INSTITUTET
Organization address
address: Nobels Vag 5 contact info |
SE (STOCKHOLM) | coordinator | 179˙223.80 |
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Obiettivo del progetto (Objective)
'Only a subset of tumour cells is capable of giving rise to new tumours. These so called “tumour stem-cells” are functionally similar to adult stem cells and have been identified in tumours of several tissues. Whether transformation of adult stem cells into tumour stem cells is the event leading to the disease is not clear. Alternatively, tumours could arise from the population of committed progenitors, which have de novo acquired self-renewal properties. The aim of the proposed project is to investigate the role of Hedgehog (Hh) signalling in mammary gland stem/progenitor cell fate and cancer development. The following questions will be addressed: 1. Does induction of Gli1 expression expand the stem/progenitor cell population in the mammary gland and are the functional properties of these cells changed? 2. Does induction of Gli1 expression expand the population of Lgr5 cells in Gli expressing mammary glands and Gli1 induced tumours? 3. Does induction of Gli1 expression result in additional genetic changes relevant for tumour formation? 4. Does induction of Hh-signalling in Lgr5 mammary cells cause tumour formation? 5. Would prevention of Gli activation with small molecule inhibitors like GANT61 prevent mammary cancer formation? The activity of the Hh pathway is required for growth of a variety of tumours, including breast cancer. We propose to use tetracycline-controlled conditional expression of Gli1, the main effector of the Hh-signalling pathway, in mouse mammary gland as a model system. The dynamic changes in the stem/progenitor cell population will be monitored after induction of Gli1 expression. Stem cells will be sorted based on known markers, including the orphan G protein coupled receptor Lgr5. The role of Hh signalling in Lgr5 cells and the tumorigenecity of Lgr5 cells will be addressed. This project will contribute to our understanding of breast cancer development and have implications on future therapeutic strategies of mammary cancer.'
Introduzione (Teaser)
An EU-funded research project has shed light on the tumour-growth role of a key-signalling pathway in mammary gland stem cells.
Descrizione progetto (Article)
Tumour stem cells (TSCs) identified in several tumour tissues are functionally similar to mature stem cells, and are capable of creating new tumours. TSCs are thought to originate from either transformed adult stem cells or progenitor cells.
The hedgehog (Hh) signalling pathway gives stem cells the required information to differentiate. Different kinds of cells have different concentrations of Hedgehog proteins. Malfunction of the pathway can result in diseases like cancer.
The aim of the EU-funded Mammahoglgr project was to further investigate the Hh signalling pathway supporting tumour-growth role in gland stem/progenitor cell fate and cancer development.
In the framework of this project, unique and innovative tools were established. A mouse model with conditionally regulated Hh-pathway activation was created in the mammary gland. This model was used for monitoring the dynamic changes in the stem/progenitor cell population.
Furthermore, an innovative tumour mouse line was developed, in which the Hh-pathway could be activated and deactivated. This cell line promises to shed light on the early stages of tumour development and identify the cancer-initiating cells.
The results showed a significant increase in tumour formation and growth rate upon Hh-pathway activation. Additionally, stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) was over-expressed in and induced by Hh pathway activation tumours, suggesting that these tumours are less differentiated. Therefore, the system of induced tumours developed within Mammahoglgr project represents a relevant model to investigate the role of the Hh-pathway in breast cancer.
The confirmation of the role of an activated Hh-pathway in the development of breast cancer and the tools developed will guide the therapeutic strategies to new, specifically targeted drugs.