Epithelial stem and progenitor cells: responses to homeostatic and oncogenic cues
Kadur Lakshminarasimha Murthy, Preetish
In this study we have tried to understand the epithelial tissue, which froms the barrier between the external environment and the body, in homeostatic and oncogenic states. Notch signalling maintains epithelial stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. In the first part of this dissertation, we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage. Hence, in the intestinal epithelium, Fringes are present in the ligand-presenting ‘sender’ secretory cells and promote Notch activity in the neighbouring ‘receiver’ cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus. Mutations in the KRAS gene are frequently found in human lung tumours and are known to drive their proliferation. In the second half of this study, we show that mutant Kras remodels the epigenetic landscape of Club and AEC2 cells of the lung. We find that FOSL1 based AP-1 transcription factor directly binds to and guides the nucleosome remodelling SWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. Pharmacological inhibition of AP-1 activity abrogated proliferation specifically of tumour cells but not normal cells. We observe that tumours retain a signature of their cell of origin and demonstrate that AP-1 mediated epigenetic reprogramming is not restricted to pulmonary epithelium but can also be seen in intestinal stem cells, suggesting that it is a general mechanism downstream of mutant Kras.
Intestinal Stem Cell; Kras; Lunatic Fringe; Lung Adenocarcinoma; Mechanical engineering
Shen, Xiling; Singh, Ankur
Ph.D., Mechanical Engineering
Doctor of Philosophy
dissertation or thesis