Silva Rodrigues, Felipe;
(2024)
A bidirectional relationship between metastatic cancer
outgrowth and tissue stemness in the lung.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Thesis FRodrigues.pdf - Accepted Version Download (54MB) | Preview |
Abstract
The interaction between cancer cells and their microenvironment (niche) is vital for every aspect of cancer progression, including metastasis. During metastatic outgrowth, disseminated tumour cells perturb the host tissue to initiate the formation of a niche that supports the long-term proliferative potential of cancer cells. However, the fundamental cellular processes that take place during the initiation of the metastatic niche are poorly understood. Here, by focusing on breast cancer metastasis to the lung, I have characterised the activation of a developmental-like programme in lung epithelial cells, in particular alveolar type 2 (AT2) cells, within the niche. Importantly, the activation of stem cell programmes in AT2 cells varied according to the tumour type and the metastatic competency of the cancer cells. Whilst colorectal cancer cells promote alveolar progenitor features, metastatic breast cancer cells reprogramme AT2 cells into a multilineage state. This activation of AT2 cells is accompanied by chromatin remodelling, whereby AT2 cells within the niche exhibit higher chromatin accessibility when compared to their distal counterparts outside the niche. In addition, although fibroblasts and macrophages within the niche have the potential to influence AT2 cell behaviour ex vivo, primary breast cancer cells are able to induce multilineage reprogramming of alveolar cells upon physical interaction. Mechanistically, metastatic breast cancer cells upregulate Sox9 expression upon interaction with the alveolar environment, which promote their metastasis-initiating potential. Inhibition of Sox9 expression in cancer cells results in niche epithelial cells losing their multilineage differentiation ability. Finally, alveolar epithelial cells support stemness and tumour-initiating behaviour in cancer cells demonstrated by their co-culture in tumouroid formation assays. Altogether, here it is proposed the concept of “reflected stemness” during metastatic niche initiation, whereby metastatic cells reprogramme the surrounding epithelial cells into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumourigenic programs may be amplified.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | A bidirectional relationship between metastatic cancer outgrowth and tissue stemness in the lung |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10186650 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
