2018Avhandling for graden philosophiae doctor (ph.d.)Dato for disputas: 06.04.18Trykk:Skipnes Kommunikasjon / Universitetet i Bergen Materialet i denne publikasjonen er omfattet av åndsverkslovens bestemmelser. Tittel:The effects of ageing on microenvironment-contextual epithelial cell signalling Rein Aasland, for valuable insight on academic writing, and for pointing out, as did James, when my words became self-indulgent fun and flowers. Mark LaBarge, for taking me into his lab, and letting me partake in that which concerns absolutely everyone: ageing. To Martha Stampfer for allowing me to poke around in her human cell resources biobank. To James Garbe for being an incredibly sympathetic guy with the most convenient knowledge up his sleeve.I would like to thank my mother Nina-Mamma for never curbing her enthusiasm for tiny biology when I brought home science homework, and my father Ulf for being genuinely impressed with pretty much everything I didincluding when I did it badly. I need to thank my boyfriend, Lars, for meticulous proofreading of the manuscript, and for continuously encouraging me to put my academic whims into writing. I want to point out that Iren Abrahamsen did substantial preliminary work for the microsphere cytometry method. I need to to thank my medical doctor office mates, Gry and Kjersti for valuable insights from the clinical realm where lab rats never go, to remind me who we're doing this for in the first place. Thanks to Sissel for being that steady rock in the corner stall of the lab where PhDs and postdocs fly by. I would like to thank the girls in the lab for taking up the fight against cancer cell Fråtse-Frida, and winning it. Finally, I would like to thank the Cancer Society, VilVite, CCBIO and Forskningsdagene for giving me trust, whether it was to develop flow cytometry protocols or popular science shows, or to interrogate the microenvironment I would like thank just anyone else in the lab and the general world who is interested and willing to contemplate big ideas such as the purpose of being. And at last, every single nerd: nerdy boys and nerdy girls. pathway activation levels in HMEC are attenuated with age, and that the diminished signaling magnitude in HMEC from ageing women correlated with reduced probability of activating oncogene-induced senescence.Our results suggest that attenuated cell signaling response may reduce the likelihood of activating oncogene induced senescence, for cells in ageing women. We hypothesize this is the result of age-related changes to the microenvironment that support age-emergent cellular phenotypes with increased cancer susceptibility.
Post-menopausal women are more prone to breast cancer than younger women. The increased frequency of age-related breast cancers is likely due to interactions between acquired mutations and age-dependent epigenetic changes that affect mammary epithelial lineage fidelity. We hypothesized that the aging process fundamentally affects how human mammary epithelial cells (HMEC) respond to microenvironmental signals, resulting in increased susceptibility to oncogenic transformation. In order to measure microenvironmental cell signaling in normal finite lifespan HMEC, we applied a novel microsphere-based flow cytometry technology. The microsphere cytometry allows multiparametric single cell quantification of signaling pathway activity and lineage-specific marker expression in cells adhered to surfacefunctionalized microspheres that mimic specific microenvironments. Using this approach, we analyzed age-dependent changes in human mammary myoepithelial and luminal epithelial cells exposed to different ECM and growth factors. We found that ECM-mediated MAP kinase and PI3 kinase activation levels in HMEC were attenuated with age. Older luminal cells displayed higher surface integrin levels consistent with acquired basal identity, albeit with decreased integrin activation and increased Src-signaling relative to myoepithelial cells. We show that the diminished signaling magnitude in HMEC from older women correlated with reduced probability of activating oncogeneinduced senescence. We propose that age-related changes in ECM-mediated epithelial cell regulation may impair protective tumor suppression mechanisms and increase breast cancer susceptibility.
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