| Title: |
From Derailed Development to Childhood Cancer : Using organoid models to study Malignant Rhabdoid Tumors |
| Authors: |
Custers, Lars Martinus Catherina; Clevers, J.C.; Drost, J. |
| Publisher Information: |
Utrecht University |
| Publication Year: |
2021 |
| Subject Terms: |
pediatric cancer; malignant rhabdoid tumor; embryonic development; differentiation block; differentiation therapy: chromatin remodeling; organoid; single cell RNA sequencing; genetic lineage tracing; CRISPR-Cas9 knock-out screen |
| Description: |
Further improvement in the survival of children with cancer is likely to come from therapies specifically designed to target the unique oncogenic properties of childhood cancer cells. A pediatric malignancy for which effective targeted treatment is currently lacking is malignant rhabdoid tumor (MRT), which has been the primary focus of our research presented in this Thesis. MRT is driven by a single recurrent genetic aberration, bi-allelic loss of SMARCB1 or in rare cases SMARCA4. MRT remain one of the most lethal childhood cancers. There is therefore an urgent need for novel effective treatment options. A subset of childhood malignancies, including MRT, is indicated to initiate in prenatal life. They are therefore commonly regarded as products of aberrant embryonic development. A recurrent characteristic of these so-called embryonal tumors is a block in cellular maturation that retains the cells in an embryonic, proliferative state. This embryonic profile is absent in adult cells and may therefore serve as a specific therapeutic vulnerability. For this reason, our studies aimed to identify the embryonic identity and cellular origin of MRT as well as to define the SMARCB1-dependent differentiation pathways underpinning MRT development, to uncover novel therapeutic options. Tumor transcriptomes may accommodate clues of the differentiation state and origin of human cancer. Therefore, we interrogated the differentiation state of adult and childhood renal cancers by mapping bulk tumor transcriptomes to single-cell references of normal adult and fetal cells. Our findings indicated a consistent fetal signature across childhood renal cancers, absent in adult tumors, which is supporting evidence of their aberrant developmental state. Furthermore, we studied the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues placed MRT in a lineage with neural crest-derived Schwann cells. ... |
| Document Type: |
doctoral or postdoctoral thesis |
| File Description: |
text/plain |
| Language: |
English |
| Relation: |
https://dspace.library.uu.nl/handle/1874/406627 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/406627 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.B4FDB82D |
| Database: |
BASE |