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THE IMPACT OF THE ENVIRONMENT AND ONCOGENESIS ON CANCER CELL DIVISIONS

Project description

Insight into the ability of cancer cells to divide in challenging microenvironments

Mammalian cells must round up to divide, providing the space to develop a mitotic spindle for symmetric chromosomal segregation. If mitotic rounding is impeded by physical confinement or malfunction in adhesion remodelling, mitotic cell death may ensue. The EU-funded IEOCCD project aims to identify the mechanisms that allow epithelial cancer cells to divide in a challenging physical environment. Ras-activated epithelial cells are able to round better compared to normal cells, suggesting that Ras-ERK signalling plays a role in the mitotic rounding of cancer cells. The project will study a connection between Ras-ERK signalling and mitotic progression, linking oncogenesis to the ability of cancer cells to divide in a wide range of environments.

Objective

Mammalian cells must round up to divide by remodeling their adhesions and their cytoskeleton to form a stiff actin cortex. Mitotic rounding provides the space necessary to develop a mitotic spindle to undergo symmetric chromosomal segregation. If mitotic rounding is impeded by physical confinement or preventing adhesion remodeling, defects in spindle assembly and chromosomal missegregation can lead to mitotic cell death. In cancer, the cells must divide in a challenging environment which can alter the way cells divide. Preliminary data show Ras- activated epithelial cells are able to round better compared to normal cells. This adaptation could protect the dividing cell from the physical environment and allow epithelial cancer cells to divide in the confines of the tumor and distant metastatic sites. Here, we aim to identify mechanisms that allow epithelial cancer cells to divide differently from that of normal epithelial cells. Potentially, this mechanism could be a powerful target if we are able to prevent cancer cell division without interfering with normal cell division. Preliminary data suggest Ras-ERK signalling could play a role in mitotic rounding of cancer cells. In this proposal, I will 1) investigate ERK signalling dynamics during mitotic progression, how it regulates mitotic rounding and effects on the following cell cycle 2) investigate how Ras-ERK signalling and the mechanism of cell division are affected by environment using microfabricated tools and 3) initiate oncogenic activation by over-expressing receptor tyrosine kinases commonly found over-expressed in cancer or constitutive activation of Ras/Raf and measure changes in Ras-ERK signalling and cell mechanics. By establishing a link between Ras-ERK signalling and mitotic progression, I will determine how oncogenesis affects Ras-ERK signalling dynamics and cell division to allow cancer cells to divide in a wide range of environments.

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Coordinator

UNIVERSITY COLLEGE LONDON
Net EU contribution
€ 212 933,76
Address
Gower street
WC1E 6BT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00