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Rahavi, Seyed MohammadReza

University of British Columbia

Neuroblastoma (NB), a complex pediatric cancer primarily affecting the adrenal medulla and paraspinal sympathetic ganglia, presents significant clinical challenges due to its occurrence in young children and low incidence rate. These factors complicate clinical trial recruitment, emphasizing the need for accurate pre-clinical models. My thesis aimed to enhance pre-clinical mouse models of NB to expedite the identification and assessment of new treatments for this disease. The first focus of my work was to refine the widely-used TH-MYCN transgenic mouse model. I have enabled early detection of NB progression through luciferase expression in developing tumours by employing a triple-transgenic Cre-lox approach. This modification facilitates non-invasive monitoring of tumour growth and is further leveraged to demonstrate the effectiveness of NB cell transplant experiments for establishing tumours at various organ sites. This new model overcomes previous limitations of TH-MYCN mice, including the limited metastatic spread and lack of GD2 expression on tumour-derived cell lines. Building on this approach, I next established a panel of human NB cell lines engineered for bioluminescence-based detection in xenografts. This was achieved through lentiviral transduction, allowing for the stable co-expression of luciferase and green fluorescent protein in eleven human NB cell lines. These cell line xenografts were characterized for tumour localization, growth rates, and mouse survival. This work revealed significant consistency and diversity among the different cell lines that could inform the design of future pre-clinical studies. To expand on the success of the luciferase-tagged mouse and human NB models, I lastly explored dual-colour in vivo imaging techniques. Challenges with spectral overlap were addressed through innovative approaches, combining fluorescence and bioluminescent imaging to enhance signal separation and sensitivity. This approach could contribute to immune therapy development by enabling simultaneous detection of effector and target cells. My thesis establishes novel, complementary mouse NB models that harness luciferase expression to provide real-time, non-invasive tracking of tumour growth and treatment response. These developments hold significant potential to deepen our understanding of NB biology, immune system interactions, and therapeutic susceptibility, potentially guiding future research and development of treatment approaches for NB.

Text

2024-01-12

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87269

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/