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Karolinska Institute

1. Westerlund, Isabelle. Novel aspects of neuroblastoma : to hypoxia and beyond .

Degree: 2019, Karolinska Institute

Neuroblastoma (NB) is a pediatric cancer arising from the neural crest cells forming the sympathetic nervous system. Just as other types of pediatric cancer the driving mutations of neuroblastoma are few and the tumors are instead categorized according to genetic abbreviations such as amplification, loss of heterozygosity, gains and translocations. Neuroblastoma continues to be therapeutically challenging and flabbergasts scientists and doctors with it vast heterogeneity both clinically and biologically. The tumors range from aggressive, fast growing, lethal cancer to metastatic tumors that will spontaneously regress and disappear without any clinical interventions. The survivors of high-risk neuroblastoma struggle with life-long side effects due to the aggressive therapeutic treatment used in these young children. In this thesis I have focused on discovering alternative mechanisms that can contribute to the development and malignancy of neuroblastoma. Paper I. High-risk neuroblastoma has been shown to have high level of DNA methylation of putative tumor suppressors. We designed a therapeutic strategy where we exploited the reversibility of DNA methylation and combined the DNA-demethylating drug 5-Aza- deoxycytidine (AZA) with the differentiation-promoting activity of retinoic acid (RA) as an alternative strategy to treat high-risk neuroblastoma. In this paper we showed that treatment with AZA restores high-risk neuroblastomas sensitivity to RA. Additionally, the combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival in vivo. Genomewide analysis of treated tumors revealed that the combined treatment induced a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. We performed a loss-of- function experiment using a small-molecule inhibitor of HIF2α which resulted in diminished tumor response to AZA+RA treatment. Our study indicated that the increase in HIF2α levels is a key component in the tumor response to AZA+RA and that high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis, but negatively correlate with key features of high-risk tumors. Contrary to previous studies, our findings indicate an unanticipated tumor suppressive role for HIF2α in neuroblastoma. Paper II. We explored the role of hypoxia inducible transcription factor EPAS1/HIF2α in neuroblastoma. We analyzed several neuroblastoma tumor expression datasets which showed that EPAS1 expression is associated with better patient outcome and characteristics of low- risk tumors and did not support an oncogenic role as previously shown in other studies. We continued by treating xenografted mice with HIF2α inhibitors, which did not block in vitro neuroblastoma cell proliferation nor tumor growth. To illuminate the role of EPAS1 during embryonic development we analyzed single cell data sets from the developing mouse sympathoadrenal lineage,…

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APA (6th Edition):

Westerlund, I. (2019). Novel aspects of neuroblastoma : to hypoxia and beyond . (Thesis). Karolinska Institute. Retrieved from http://hdl.handle.net/10616/46637

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Westerlund, Isabelle. “Novel aspects of neuroblastoma : to hypoxia and beyond .” 2019. Thesis, Karolinska Institute. Accessed March 20, 2019. http://hdl.handle.net/10616/46637.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Westerlund, Isabelle. “Novel aspects of neuroblastoma : to hypoxia and beyond .” 2019. Web. 20 Mar 2019.

Vancouver:

Westerlund I. Novel aspects of neuroblastoma : to hypoxia and beyond . [Internet] [Thesis]. Karolinska Institute; 2019. [cited 2019 Mar 20]. Available from: http://hdl.handle.net/10616/46637.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Westerlund I. Novel aspects of neuroblastoma : to hypoxia and beyond . [Thesis]. Karolinska Institute; 2019. Available from: http://hdl.handle.net/10616/46637

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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