Invesigating the role of RB in constraining metastasis and cell state plasticity in a tumor spheroid model
| dc.contributor.advisor | Feldser, David, M | |
| dc.contributor.author | Freeburg, Nelson | |
| dc.date.accessioned | 2024-02-01T17:10:56Z | |
| dc.date.available | 2024-02-01T17:10:56Z | |
| dc.date.copyright | 2023 | |
| dc.date.issued | 2023 | |
| dc.date.updated | 2024-02-01T17:10:57Z | |
| dc.description | 2023 | |
| dc.description.abstract | While localized cancer can often be treated, metastatic cancer has a dramatically worse prognosis. As a result, there is great interest in understanding the biological processes underlying metastatic progression. Cell state plasticity, or lineage plasticity, is a major precursor to metastasis and tumor progression in general. It is characterized by broad changes in the gene expression pattern which identifies a given cell type and often loss of expression lineage-identifying markers (lineage decommitment). In multiple cancer types, loss of the Retinoblastoma tumor suppressor (RB) results in both cell state plasticity and enhanced metastatic competency. To elucidate the link between RB, cell state plasticity, and metastasis, we produced RB-deficient tumor spheroids from murine KrasLSL-G12D/+; p53flox/flox (KP) lung adenocarcinomas in which RB could be inducibly reactivated. Interestingly, RB inactivation greatly enhanced tumor spheroid forming capability from KP lung adenocarcinomas. However, RB reactivation had no effect on the maintenance of tumor spheroid lines once established. We also found that RB-deficient tumor spheroid lines are not uniformly metastatically competent but are equally likely to be non-metastatic. Surprisingly, unlike tumor spheroid maintenance, RB restoration could functionally revert metastatic tumor spheroids to a non-metastatic cell state. Thus, therapeutic approaches which reactivate the RB pathway in lung cancer may reverse metastatic ability and have clinical utility. Finally, the acquisition of tumor spheroid forming potential reflects underlying cell state plasticity, which is often predictive of, or even conflated with metastatic ability. However, these results suggest that each is a discrete RB-regulated cell state and question the suitability of tumor spheroid models for their predictive potential of advanced metastatic tumor cell states. | |
| dc.description.degree | Doctor of Philosophy (PhD) | |
| dc.extent | 97 | |
| dc.identifier.uri | https://repository.upenn.edu/handle/20.500.14332/59417 | |
| dc.language.iso | en | |
| dc.subject | Biology | |
| dc.subject.other | Cancer | |
| dc.subject.other | Cell State Plasticity | |
| dc.subject.other | Lung Adenocarcinoma | |
| dc.subject.other | Metastasis | |
| dc.subject.other | RB | |
| dc.subject.other | Tumor Spheroid | |
| dc.title | Invesigating the role of RB in constraining metastasis and cell state plasticity in a tumor spheroid model | |
| dc.type | Dissertation/Thesis | |
| dspace.entity.type | Publication | |
| upenn.graduate.group | Cell and Molecular Biology |