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Rigshospitalet - en del af Københavns Universitetshospital

Single-cell sequencing of Glioblastomaderived tumour material to identify molecular alterations associated with aggressive disease

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling

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Glioblastoma (GBM) is a highly aggressive brain cancer with no curative treatment and short overall survival. New treatment options are therefore urgently needed, and due to the high success rates of immunotherapy observed in other cancers, it is currently being tested inclinical GBM trials.
In this thesis I focus on how GBM progression and treatment affects the tumour tissue on a single-cell level. To achieve this I performed single-cell RNA-sequencing (scRNA-seq) on paired tissue from the patient's primary and relapse surgeries, in which immunotherapy was administered prior to the relapse surgery. With this approach I obtained high resolution of the
gene expression present in different cell types and cell states within each tumour.

In total scRNA-seq was performed on eight patients from a clinical immunotherapy trial. Of these, one patient showed signs of an immunological response to therapy including upregulation of CD8+ T cells, upregulation of MHC-I signalling and a shift towards more tumour-associated macrophages and less microglia. Two additional patients showed signs of partial response, while the remaining patients did not respond to immunotherapy.

In the second manuscript of the thesis I focused on the tumour evolution of a patient with a typical GBM disease course, who underwent three surgeries, from which I performed scRNA-seq at all three time points. The scRNA-seq based evolution was broadened out by incorporating results from whole genome sequencing and Hi-C, allowing us to study multiple levels of genomics and transcriptomics changes. We observed a high level of initial
mutational evolution, followed by a more transcriptional evolution in the disease relapses, suggesting high plasticity within the tumour cells. This was supported by dynamic compartment switches in the genome folding, tumour microenvironment compositional changes, as well as an upregulation of the gene PTPRZ1 , known to be involved in stem-cell regulation.

In conclusion, I demonstrated the advantages of using scRNA-seq to characterise GBM tissue. In the first manuscript we identified a subset of patients that showed several signs of immune activation. In the second manuscript we deconvoluted the tumour evolution into an early mutational part and a later tumour microenvironment-dependent part, illustrating that
the tumour progression is influenced by surrounding cells and the genomic conformation.
ForlagEget Forlag
Antal sider109
StatusUdgivet - 15 jun. 2022

ID: 79068150