TY - JOUR
T1 - Spatial transcriptomic comparisons of glioblastoma tissue reveal upregulation of neurodevelopmental pathways and synaptic genes in infiltrating tumor cells
AU - Harwood, Dylan
AU - Pedersen, Vilde
AU - Bager, Nicolai
AU - Schmidt, Ane
AU - Stannius, Tobias
AU - Areskeviciute, Ausrine
AU - Josefsen, Knud
AU - Noroxe, Dorte
AU - Scheie, David
AU - Rostalski, Hannah
AU - Lue, Maya
AU - Locallo, Alessio
AU - Lassen, Ulrik
AU - Bagger, Frederik
AU - Weischenfeldt, Joachim
AU - Heiland, Dieter
AU - Vitting-Seerup, Kristoffer
AU - Michaelsen, Signe
AU - Kristensen, Bjarne
PY - 2024
Y1 - 2024
N2 - Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, chemotherapy, and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Gene expression profiling allows glioblastoma tumor cores to be classified into mesenchymal, proneural, and classical subtypes, each with distinct genetic alterations and cellular compositions. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using single-cell and multicellular resolution spatial transcriptomics on tissues from both the tumor core and infiltrated brain tissue (n = 11), we compared the transcriptional profiles of malignant cells in these regions. Malignant cells near regions with microvascular proliferation showed increased expression of genes related to vascular homeostasis. Within tumor cores, proneural and mesenchymal subtypes exhibited distinct spatial gene expression patterns, although these differences were reduced in the infiltrated brain tissue, apart from gene expression due to chromosomal alterations specific to the proneural subtype. We identified two transcriptional patterns of brain infiltration, with the dominant pattern showing a transition from mesenchymal to proneural states. This transition was accompanied by increased expression of genes linked to neurodevelopmental pathways and glial cell differentiation. Additionally, one gene module upregulated in infiltrating malignant cells was predictive of poor patient survival and enriched for genes associated with differentiated neuronal cells. Together, our findings provide an updated view of the spatial landscape of glioblastomas and infiltrated brain tissue, furthering our understanding of the malignant cells that invade healthy brain. This insight offers new avenues for targeted therapy after surgical resection of the primary tumor.
AB - Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, chemotherapy, and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Gene expression profiling allows glioblastoma tumor cores to be classified into mesenchymal, proneural, and classical subtypes, each with distinct genetic alterations and cellular compositions. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using single-cell and multicellular resolution spatial transcriptomics on tissues from both the tumor core and infiltrated brain tissue (n = 11), we compared the transcriptional profiles of malignant cells in these regions. Malignant cells near regions with microvascular proliferation showed increased expression of genes related to vascular homeostasis. Within tumor cores, proneural and mesenchymal subtypes exhibited distinct spatial gene expression patterns, although these differences were reduced in the infiltrated brain tissue, apart from gene expression due to chromosomal alterations specific to the proneural subtype. We identified two transcriptional patterns of brain infiltration, with the dominant pattern showing a transition from mesenchymal to proneural states. This transition was accompanied by increased expression of genes linked to neurodevelopmental pathways and glial cell differentiation. Additionally, one gene module upregulated in infiltrating malignant cells was predictive of poor patient survival and enriched for genes associated with differentiated neuronal cells. Together, our findings provide an updated view of the spatial landscape of glioblastomas and infiltrated brain tissue, furthering our understanding of the malignant cells that invade healthy brain. This insight offers new avenues for targeted therapy after surgical resection of the primary tumor.
U2 - 10.1093/neuonc/noae165.0067
DO - 10.1093/neuonc/noae165.0067
M3 - Journal article
SN - 1522-8517
VL - 26
SP - viii17-viii17
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - Suppl. 8
M1 - NOAE165.0067
ER -