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.

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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 > Institute 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
Embargo Date: 24 April 2022
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: 15 Jul 2019 11:36
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