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dc.contributor.advisorBakal, C
dc.contributor.authorPascual Vargas, P
dc.date.accessioned2020-03-05T09:00:53Z
dc.date.issued2020-03-31
dc.identifier.citation2020
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3534
dc.description.abstractDynamical remodelling of the cytoskeleton is essential for triple negative breast cancer metastasis (TNBC). Cell shape is regulated by RhoGEFs which activate Rho GTPases resulting in changes in actin polymerisation, contractility, and adhesion. The transcriptional coactivators YAP/TAZ are key effectors of RhoGEF-Rho signalling, which regulate the transcription of genes underpinning invasion. However which RhoGEFs are dysregulated in TNBC, and how they couple TNBC cell shape to YAP/TAZ activity driving invasion is unclear. To identify RhoGEF/GAPs essential for the cell shape changes driving TNBC, and those that do so by regulating YAP/TAZ, we performed high-throughput RNAi screens of 142 siRNAs targeting human RhoGEF/GAPs. We identified RhoGEF/GAPs which regulate cell shape specifically in the highly metastatic cell line LM2, its less metastatic parental counterpart MDA-MB-231, and in both cell lines. We found that the shape space that LM2 cells explore is very distinct to that of MDA-MB-231. Further, we identified RhoGEFs which regulate YAP/TAZ in LM2, and whether they do so in shape-dependent or independent ways. We also found that more spindly-like TNBC cell lines have high levels of YAP/TAZ activation compared to more spread-like TNBC cell lines. We propose that LM2 celss' ability to dynamically change shape is mediated by a specific set of RhoGEF/GAPs, coupled to their ability to downregulate predominantly active YAP/TAZ in rsponse to their environment, underlies their metastatic nature. We identified the RhoGEF DOCK4, as a regulator of invasion via YAP/TAZ in LM2 cells. We propose that DOCK5 coordinates leading edge with microtubule dynamics and adhesions, driving invasion through YAP/TAZ, and therefore is an attractive therapeutic target.
dc.languageeng
dc.language.isoeng
dc.publisherInstitute of Cancer Research (University Of London)
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectTheses, Doctoral
dc.subjectBreast Cancer - Biology
dc.subjectBreast Cancer - Genetics
dc.titleHow RhoGEFs drive triple negative breast cancer cell invasion through the activation of YAP and TAZ
dc.typeThesis or Dissertation
dcterms.accessRightsPublic
dcterms.licensehttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-03-31
rioxxterms.typeThesis
pubs.notes6 months
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Dynamical Cell Systems
pubs.embargo.terms6 months
icr.researchteamDynamical Cell Systemsen_US
dc.contributor.icrauthorPascual Vargas, Patriciaen
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelDoctoral
uketdterms.qualificationnamePh.D
icr.provenanceDeposited by Mr Arek Surman (impersonating Miss Patricia Pascual Vargas) on 2022-07-21. Deposit type is subsequent. No. of files: 1. Files: PhD Thesis Pascual Vargas Patricia (compressed).pdf
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePh.D


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