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Negative regulation of interferon lambda induced JAK-STAT signaling and development of patient-derived xenograft models from fresh human hepatocellular carcinoma biopsies

Blumer, Tanja. Negative regulation of interferon lambda induced JAK-STAT signaling and development of patient-derived xenograft models from fresh human hepatocellular carcinoma biopsies. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12647

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Abstract

Type I and type III interferons (IFNs) act as the first line of defense against invading pathogens by inducing a fast and strong host response characterized by the expression of hundreds of interferon stimulated genes (ISGs). However, the magnitude and duration of cellular responses to viral and bacterial infections needs to be controlled properly to maintain tissue homeostasis. Ubiquitin specific peptidase 18 (USP18), suppressor of cytokine signaling 1 (SOCS1) and SOCS3 are the three known inducible negative regulators of the IFN-α induced signaling cascade. However, the role of USP18 on IFN-λ signaling is a matter of controversy. Furthermore, the physiological relevance of the relative contribution of SOCS1 and SOCS3 on in vitro IFN-λ signaling needs to be validated in vivo. Thus, we aimed to investigate the role of USP18, SOCS1 and SOCS3 on the IFN-λ induced signaling cascade both in vitro and in vivo.
Based on experiments with USP18, SOCS1 and SOCS3 knockout cells, we demonstrated that USP18 is the major negative regulator of IFN-α induced JAK-STAT signaling whereas IFN-λ is negatively regulated by SOCS1. Furthermore, using USP18 and SOCS1 knockout mice, we confirmed USP18 and SOCS1 as physiological relevant negative regulators of IFN-α and IFN-λ, respectively. Importantly, we demonstrated that negative regulation of IFN-α was strong and immediate while that for IFN-λ was more subtle both in kinetics as well as magnitude. Taken together, our results suggest that the differences in negative regulations are the basis for the distinct kinetic properties of IFN-α and IFN-λ signaling reflecting their specific functions. IFN-α signaling provides a powerful and immediate defense system against systemic infections but has to be controlled tightly to maintain tissue homeostasis. Therefore a strong negative regulator like USP18 that completely shuts down the system is needed. By contrast, IFN-λ provides a continuous first line defense in mucosal epithelial cells that are constantly exposed to pathogens. Thus, SOCS1 facilitates a maintained but controlled IFN-λ signaling that allows fighting invading pathogens without loosing tissue homeostasis.
Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide with yearly increasing incidence and unsatisfying treatment options. Thus, there is a clear need for new and more efficient drugs for the treatment of HCC. A major obstacle for the understanding of the pathogenesis of HCC is the lack of an efficient in vivo model that accurately reflects the broad spectrum of human HCC. Patient-derived xenograft (PDX) models gained a lot of interest in pre-clinical studies of anti-cancer drugs. Indeed, several HCC PDX models have been established in recent years. However, all these models are derived from resected HCC specimen and therefore limited to early stage disease. Patients with advanced stage HCC are not represented, although they would benefit most from new treatment options. Therefore, we aimed to generate HCC PDX models from fresh human HCC biopsies that cover all disease stages, with special interest in advanced stage HCC.
We successfully established and passaged eleven HCC PDX mouse models from patients presenting with all major underlying liver diseases. The biopsies that successfully engrafted were representative of the spectrum of poorly differentiated HCCs, including both early and late-stage disease. Importantly, the PDX models recapitulated tumor morphology, differentiation grade and the expression pattern of known HCC markers. Finally, RNA sequencing analyses demonstrated that our PDX models maintained the transcriptomic profiles and expression of somatic mutations of their originating tumors over at least four generations. Taken together, these novel HCC PDX models do not only allow investigation of the biology of all stages of HCC but also the study of drug-induced resistance mechanisms and the development of new HCC therapies.
Advisors:Heim, Markus H. and Christofori, Gerhard M.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
05 Faculty of Science
UniBasel Contributors:Heim, Markus H. and Christofori, Gerhard M.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12647
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (164 Seiten)
Language:English
Identification Number:
Last Modified:29 Jun 2018 04:30
Deposited On:28 Jun 2018 08:30

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