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Regulatory mechanisms controlling a new mechanical Epithelial to Mesenchymal Transition in zebrafish

Project description

Dissecting the process of epithelial to mesenchymal transition

Epithelial to mesenchymal transition (EMT) is a process implicated in cancer metastasis that allows cells to detach from the tissue of origin and enter the circulation. Researchers of the EU-funded MechTransition project have challenged previous conceptions that developmental EMT programmes participate in cancer as well, proposing a mechanical process instead. During MechTransition, they aim to further delineate the mechanism of EMT and investigate the impact of mechanical stress on cancer progression. Results will shed light on how invading cells colonise specific tissues and help identify the drivers of this process, paving the way for novel interventions against metastatic disease.

Objective

While cancer biologists have long assumed that developmental Epithelial to Mesenchymal Transitions (EMT) transcriptional programs also control cancer metastasis, our lab has recently found that cancer EMT instead uses a mechanical-based two-step process. Typically, epithelial cells fated to die get extruded apically into the lumen. However, oncogenic mutations that drive metastatic cancers hijack this process, causing cells to either form masses or to extrude basally back into the tissue at separate sites. Basal extrusion causes transformed cells to not only invade but also to lose their entire apical membranes, including their E-cadherins, which are critical to epithelial identity. Later, invading cells migrate using a stable-bleb type motility typical of cells in confined spaces and then transdifferentiate into a variety of different cell types. While our lab has established that basal extrusion causes invasion and loss of epithelial identity, it is unclear what later causes cells to become mesenchymal. Using the transparent zebrafish embryo, I will investigate the mechanisms that promote the second step of EMT by answering the following questions: 1) Does mechanical stress following basal extrusion cause trans-differentiation of invading cells? 2) What programs promote EMT of transformed cells? 3) What environments allow invading cells to colonise specific tissues? Our new EMT model represents a paradigm shift in our understanding of how tumour cells initiate metastasis, survive in different environments, and become distinct cell types. Thus, addressing these aims could impact our ability to finally treat metastatic disease.

Coordinator

KING'S COLLEGE LONDON
Net EU contribution
€ 224 933,76
Address
STRAND
WC2R 2LS London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 224 933,76