TY - JOUR
T1 - Cellular diversity through space and time
T2 - adding new dimensions to GBM therapeutic development
AU - Johnson, Amanda L.
AU - Lopez-Bertoni, Hernando
N1 - Publisher Copyright:
Copyright © 2024 Johnson and Lopez-Bertoni.
PY - 2024
Y1 - 2024
N2 - The current median survival for glioblastoma (GBM) patients is only about 16 months, with many patients succumbing to the disease in just a matter of months, making it the most common and aggressive primary brain cancer in adults. This poor outcome is, in part, due to the lack of new treatment options with only one FDA-approved treatment in the last decade. Advances in sequencing techniques and transcriptomic analyses have revealed a vast degree of heterogeneity in GBM, from inter-patient diversity to intra-tumoral cellular variability. These cutting-edge approaches are providing new molecular insights highlighting a critical role for the tumor microenvironment (TME) as a driver of cellular plasticity and phenotypic heterogeneity. With this expanded molecular toolbox, the influence of TME factors, including endogenous (e.g., oxygen and nutrient availability and interactions with non-malignant cells) and iatrogenically induced (e.g., post-therapeutic intervention) stimuli, on tumor cell states can be explored to a greater depth. There exists a critical need for interrogating the temporal and spatial aspects of patient tumors at a high, cell-level resolution to identify therapeutically targetable states, interactions and mechanisms. In this review, we discuss advancements in our understanding of spatiotemporal diversity in GBM with an emphasis on the influence of hypoxia and immune cell interactions on tumor cell heterogeneity. Additionally, we describe specific high-resolution spatially resolved methodologies and their potential to expand the impact of pre-clinical GBM studies. Finally, we highlight clinical attempts at targeting hypoxia- and immune-related mechanisms of malignancy and the potential therapeutic opportunities afforded by single-cell and spatial exploration of GBM patient specimens.
AB - The current median survival for glioblastoma (GBM) patients is only about 16 months, with many patients succumbing to the disease in just a matter of months, making it the most common and aggressive primary brain cancer in adults. This poor outcome is, in part, due to the lack of new treatment options with only one FDA-approved treatment in the last decade. Advances in sequencing techniques and transcriptomic analyses have revealed a vast degree of heterogeneity in GBM, from inter-patient diversity to intra-tumoral cellular variability. These cutting-edge approaches are providing new molecular insights highlighting a critical role for the tumor microenvironment (TME) as a driver of cellular plasticity and phenotypic heterogeneity. With this expanded molecular toolbox, the influence of TME factors, including endogenous (e.g., oxygen and nutrient availability and interactions with non-malignant cells) and iatrogenically induced (e.g., post-therapeutic intervention) stimuli, on tumor cell states can be explored to a greater depth. There exists a critical need for interrogating the temporal and spatial aspects of patient tumors at a high, cell-level resolution to identify therapeutically targetable states, interactions and mechanisms. In this review, we discuss advancements in our understanding of spatiotemporal diversity in GBM with an emphasis on the influence of hypoxia and immune cell interactions on tumor cell heterogeneity. Additionally, we describe specific high-resolution spatially resolved methodologies and their potential to expand the impact of pre-clinical GBM studies. Finally, we highlight clinical attempts at targeting hypoxia- and immune-related mechanisms of malignancy and the potential therapeutic opportunities afforded by single-cell and spatial exploration of GBM patient specimens.
KW - cancer therapeutics
KW - cellular plasticity
KW - glioblastoma
KW - heterogeneity
KW - hypoxia
KW - immunotherapy
KW - single-cell sequencing
KW - spatial omics
UR - http://www.scopus.com/inward/record.url?scp=85193686596&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85193686596&partnerID=8YFLogxK
U2 - 10.3389/fgene.2024.1356611
DO - 10.3389/fgene.2024.1356611
M3 - Review article
C2 - 38774283
AN - SCOPUS:85193686596
SN - 1664-8021
VL - 15
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 1356611
ER -