Campos Leite, Taiana
(2024)
Characterization of the Inducible Multifluorescent Osteosarcoma Mouse and Investigation of the Molecular Signature of Osteosarcoma Metastatic Disease.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Osteosarcoma (OS) is the most common primary bone cancer, occurring most frequently in the pediatric population. Despite marked evolution in treatment for localized lesions throughout the last decades, the 5-year survival rate for metastatic OS remains as low as it did 30 years ago, at around 20%. Therefore, there is an urgent need to better investigate the OS metastatic process and to identify and test new therapies. Mouse models have been widely used for many years to study cancer, including OS; however, this use is limited by several factors, including immunosuppression of mice and the reliance on cell lines that have accumulated additional mutations throughout the years. Given these issues, we hypothesized that a genetically engineered mouse with postnatally induced inactivation of tumor suppressor genes p53 and Rb1 would prove to be a better model to investigate OS development and spread compared to previous models, as it would exhibit a more similar clinical behavior to human OS, while maintaining histological features and high penetrance. We also hypothesized that the least differentiated cells from OS tumors in an OS mouse model would be the most metastatic types. Lastly, we hypothesized that Osx-expressing metastatic tumor cells from the multifluorescent OS (mfOS – Prx1-CreER-EGFP+/+;Osx-mCherry+/+;Col1-CFP+/+;p53lox/lox;Rb1lox/lox) mouse model would reveal specific targetable canonical signaling pathways. To inquire into these hypotheses, we designed three specific aims. The first one was to characterize the inducible mfOS mouse clinically and histologically. After developing, monitoring, and characterizing the mfOS mouse, we demonstrated that it is more similar to human OS clinically and histologically compared to previous models. The second aim was to characterize the fluorescent cell distribution in the mfOS mouse. We showed that this mouse model can be analyzed through multiple fluorescence-based imaging techniques and observed that the most metastatic cells were Osx-expressing cells. The last aim was to determine the identity and molecular signature of varied OS cell populations in the mfOS mouse. Through single cell RNA-sequencing, we revealed cell types present in OS tumors in different stages of development and further analyzed Osx-expressing tumor cells to identify pathways that can be explored in future studies to differentially target metastatic OS cells.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 August 2024 |
| Date Type: |
Publication |
| Defense Date: |
24 July 2024 |
| Approval Date: |
26 August 2024 |
| Submission Date: |
29 July 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
140 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Dental Medicine > Dental Science |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Osteosarcoma; mouse model; transgenic; fluorochrome |
| Date Deposited: |
26 Aug 2024 14:14 |
| Last Modified: |
26 Aug 2024 14:14 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46680 |
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