- Author
-
T.J.B. van Groningen
- Title
- Intra-tumor heterogeneity and lineage plasticity in neuroblastoma
- Supervisors
-
R. Versteeg
- Co-supervisors
-
W.J. van Nes
- Award date
- 22 January 2020
- Number of pages
- 191
- ISBN
- 9789463756617
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system. After initial therapy, high stage neuroblastoma usually go in complete remission. However, the majority of these tumors relapse within five years as therapy-resistant lethal disease. Despite intensive treatment, survival has only moderately improved over the last 25 years. The mechanism how neuroblastoma cells can escape from therapy and re-emerge as therapy-resistant relapse is unknown.
In this thesis we explored intra-tumor phenotypic heterogeneity in neuroblastoma and identified tumor cells of adrenergic (ADRN) and mesenchymal (MES) fates. MES cells resembled a primitive neural crest stage, whereas ADRN cells conform to a differentiated adrenergic phenotype. We studied epigenetic mechanisms underlying plasticity of these cell types in neuroblastoma. MES and ADRN cells are each marked by unique sets of lineage-specific super-enhancers (SEs). These cell type specific SEs are associated with TFs that constitute the Core Regulatory Circuitry (CRC) for each cell type. MES-CRC TFs are capable of inducing ADRN to MES transitions in neuroblastoma cells. In addition, we examined how heterogeneity of these cell types contributed to chemotherapy and retinoic acid resistance. Our data suggests that novel therapies should target the full spectrum of neuroblastoma cell types. - Persistent Identifier
- https://hdl.handle.net/11245.1/3c2d52df-4d2c-4541-8d5b-9a7977c8c9c7
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: Introduction
Chapter 2: Neuroblastoma is composed of two super-enhancer-associated differentiation states
Chapter 3: A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma
Chapter 4: An immature subset of neuroblastoma cells synthesizes retinoic acid and is resistant to treatment with this metabolite
Chapter 5: PDGFRβ signaling controls chemotherapy resistance in MES-type neuroblastoma cells
Chapter 6: General discussion
Chapter 7: English summary; Nederlandse samenvatting; Dankwoord; Curriculum vitae; Portfolio
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