Genetically engineered Mouse Models reveal a tumourigenic collaboration between Sdhb deficiency and oncogenic Hras

Däbritz, Jan Henry Matthias (2019) Genetically engineered Mouse Models reveal a tumourigenic collaboration between Sdhb deficiency and oncogenic Hras. PhD thesis, University of Glasgow.

Abstract

The mitochondrial tumour suppressor succinate dehydrogenase is found inactivated in several tumour entities, amongst them SDH–deficient renal cell carcinoma (RCC) and pheochromocytoma/paraganglioma (Pheo/PGL). An in-depth understanding of cooperating events that enable malignant transformation of SDH-deficient tissues and preclinical model systems of SDH-deficient malignancies are still lacking. The first major goal of this thesis project was to generate a genetically engineered model of SDH-deficient RCC as an easy-to-monitor pathology in mice. In addition, we set out to study tissue-specific phenotypes resulting from stochastic Sdhb loss in peripheral organs. Driven by a Cadherin 16 promoter (KspCre) and thus in the distal renal tubular system, a fatal cystic degeneration of Sdhbfl/fl kidneys resulted from Cre expression. Ongoing untargeted metabolomics analyses of kidney, plasma and urine specimens obtained from this model hold potential for discovery of new biomarkers of SDH-deficient tumours. In a RosaCreERT2-based model, dramatic weight loss within the first weeks after transgene induction correlated with succinate accumulation in peripheral organs of Sdhbfl/fl, Hraswt/wt animals. Less intense transgene induction schemes resulted in long-term survival irrespective of Sdhb status. To the best of my knowledge, this work describes the first, albeit not perfect, genetically engineered mouse model of SDH-deficient RCC. Ongoing experimental efforts focus on reliable identification of systemic metabolic biomarkers that could improve monitoring of patients who are at (relapse) risk of SDH-deficient tumours.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Cancer, genetically engineered mouse model, metabolism, metabolomics, renal cell carcinoma, succinate dehydrogenase.
• Subjects: R Medicine > RC Internal medicine; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Funder's Name: Beatson Institute for Cancer Research (BICR)
• Supervisor's Name: Gottlieb, Professor Eyal
• Date of Award: 2019
• Depositing User: Dr. Jan Henry Matthias Däbritz
• Unique ID: glathesis:2019-41185
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 Apr 2019 09:51
• Last Modified: 27 Apr 2022 07:53
• Thesis DOI: 10.5525/gla.thesis.41185
• URI: https://theses.gla.ac.uk/id/eprint/41185

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