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Details of Grant 

EPSRC Reference: EP/T003103/1
Title: Stochastic fluctuations during mammary development and breast cancer morphogenesis
Principal Investigator: Salbreux, Dr G
Other Investigators:
Dunsby, Dr CW Behrens, Dr AA
Researcher Co-Investigators:
Project Partners:
Department: Research
Organisation: The Francis Crick Institute
Scheme: Standard Research
Starts: 01 April 2019 Ends: 30 September 2022 Value (£): 1,517,920
EPSRC Research Topic Classifications:
Analytical Science Biophysics
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
Panel History:
Panel DatePanel NameOutcome
19 Mar 2019 Building Collaboration at the Physics of Life Interface Announced
Summary on Grant Application Form
We all know from everyday experience that parts of our body can have slightly different shapes. Some of this variance is due to differences in genes, but some is also due to natural variability. This variability, where the same genetic program within cells can lead to slightly different results, arises from random (stochastic) physical processes in cells. Although determined by the same genetic program, healthy and diseased organs show a variety of shapes and forms. At present the variability exhibited by tissues is not well understood. In this proposal we will quantify and analyse the stochasticity underlying the adoption of three-dimensional shapes by multicellular structures. We anticipate that our work will identify fundamental principles governing organ and cancer development.

Part of the variability that we intend to explore arises from how cells exert forces and interact mechanically with each other, and part of it arises from the dynamics of stem cells. Cells use their cytoskeleton, an internal architecture capable of exerting forces, to move relative to each other. In addition, stem cells ensure that tissues function properly by dividing and giving rise to different cell types. For example, stem cells replace damaged cells during the repair of injured organs. Also in cancer there are stem cells, so call cancer stem cells, and these cancer stem cells (CSC) are believed to be required for cancer to spread to other sites in the body (metastasis) and are also linked to the re-emergence of cancer (relapse) after therapy.

It is not currently possible to investigate the position and the behaviour of all cells in a living animal organ. In the last few years it has become possible to culture small organ-like structures and cancers in 3 dimensions, in so-called organoids. The cellular functions and interplay in organoids is very similar to what is observed in a living animal, thus organoids represent a unique system to study the collective behaviour of cells.

Here we will explore how tissue variability in mammary gland organoids arises from mechanical forces exerted by cells on each other, and how stem cells divide and give rise to other cell types. We will look at mammary gland organoids because breast cancer is a very common disease and affects 1 in 7 woman. To do this, we will develop a system to image organoids over a prolonged period of time and use it to investigate where the stem cells are, how they divide, what type of progeny cells they generate, and how stem and progeny cells exert forces inside the organoid, to produce different organ and cancer shapes. This imaging will be performed using a custom-built microscope, and the analysis be performed using sophisticated computational and physical modelling approaches.

We will then use methods from physical sciences and numerical simulations to understand how the uncertainty in cellular behaviour results in variability of tissue shapes. Mathematical tools from theoretical physics allow to connect the behaviour of a physical system at different scales. By using a multidisciplinary approach, we will apply these tools to address the question of organ-scale variability.
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