Show simple item record

dc.contributor.authorDabrowska, Catherine
dc.date.accessioned2022-02-22T20:10:08Z
dc.date.available2022-02-22T20:10:08Z
dc.date.submitted2022-02-20
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334334
dc.description.abstractThe histological changes which occur in the step-wise progression from a normal pseudostratified airway epithelium to lung squamous cell carcinoma in situ are well documented. However, the contribution of mutated tissue stem or progenitor cells to this process are poorly understood at the level of clonal resolution. Secretory cells are known progenitor cells of the pseudostratified airway epithelium, however their clonal dynamics in homeostasis are unknown. Here, I elucidate their contribution to homeostasis, and reveal they are more persistent in the epithelium than previously predicted. Single mutations cannot consistently give rise to lung squamous cell carcinoma, however why this is the case is not known. Hyperactivation of the PI3K pathway is one of the earliest events in lung squamous cell carcinoma development. As such, I generate a novel lineage tracing mouse line, Red2-PIK3CAH1047R, which allows for the simultaneous lineage tracing of PIK3CAH1047R mutant cells and tissue-sharing wild-type cells. I then initiate recombination of the reporter in a starting population of basal cells, the known stem cell of the pseudostratified airway epithelium, or secretory cells, known progenitors. I reveal that in both lineage traces, PIK3CAH1047R mutant cells can differentiate into typical lineage trajectories, although they do form larger clones than tissue sharing counterparts. Conversely, the clonal dynamics of wild-type tissue-sharing counterparts do not alter from homeostatic behaviour. These findings were confirmed with single cell RNA sequencing, which also indicates reduced signalling between SecC-derived PIK3CAH1047R mutant cells and tissue-sharing basal cells. I also performed a detailed analysis examining the ability of intralobar secretory cells with constitutive Notch signalling to contribute to the alveolar lineages after injury. Bronchiolisation of the alveoli is observed in human diseases which impair alveolar function, such as idiopathic pulmonary fibrosis. I show that constitutive Notch signalling in intralobar secretory cells allows them to leave their airway compartment, enter the alveolar region, but fail to properly differentiate. Therefore, in my doctoral studies, I make a novel contribution to the field, including: (1) defining the clonal dynamics of secretory cells in the pseudostratified airway epithelium, (2) generating and validating a novel lineage tracing mouse line, Red2-PIK3CAH1047R, (3) defining the changes induced by PIK3CAH1047R mutation in basal cells and secretory cells of the pseudostratified airway epithelium, and (4) defining the effect of constitutive Notch signalling abrogating the capacity of intralobar secretory cells to repair the alveolar epithelium.
dc.rightsAll Rights Reserved
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/
dc.subjectclonal dynamics
dc.subjectpulmonary epithelium
dc.subjectbasal cell
dc.subjectsecretory cell
dc.subjectRed2-Onco
dc.subjectlung cancer
dc.subjectlung squamous cell carcinoma
dc.subjectPI3K
dc.subjectNotch
dc.subjecttracheal epithelium
dc.subjectdistal lung
dc.subjectbiophysical modelling
dc.subjectsingle cell
dc.subjectsingle cell RNA sequencing
dc.subjecttrachea
dc.titleStem and Progenitor Cells in Homeostatic Maintenance and Perturbation of the Pulmonary Epithelium
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.date.updated2022-02-20T19:07:40Z
dc.identifier.doi10.17863/CAM.81747
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved/
rioxxterms.typeThesis
pubs.funder-project-idCancer Research UK (S_3582)
cam.supervisorLee, Joo-Hyeon
cam.supervisorSimons, Ben
cam.supervisor.orcidSimons, Benjamin [0000-0002-3875-7071]
cam.depositDate2022-02-20
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-02-22


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record