Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

Abstract

Glioblastomas (GBM) are the most common and aggressive tumors of the central nervous system. Rapid tumor growth and diffuse infiltration into healthy brain tissue, along with high intratumoral heterogeneity, challenge therapeutic efficacy and prognosis. A better understanding of spatiotemporal tumor heterogeneity at the histological, cellular, molecular, and dynamic levels would accelerate the development of novel treatments for this devastating brain cancer. Histologically, GBM is characterized by nuclear atypia, cellular pleomorphism, necrosis, microvascular proliferation, and pseudopalisades. At the cellular level, the glioma microenvironment comprises a heterogeneous landscape of cell populations, including tumor cells, non-transformed/reactive glial and neural cells, immune cells, mesenchymal cells, and stem cells, which support tumor growth and invasion through complex network crosstalk. Genomic and transcriptomic analyses of gliomas have revealed significant inter and intratumoral heterogeneity and insights into their molecular pathogenesis. Moreover, recent evidence suggests that diverse dynamics of collective motion patterns exist in glioma tumors, which correlate with histological features. We hypothesize that glioma heterogeneity is not stochastic, but rather arises from organized and dynamic attributes, which favor glioma malignancy and influences treatment regimens. This review highlights the importance of an integrative approach of glioma histopathological features, single-cell and spatially resolved transcriptomic and cellular dynamics to understand tumor heterogeneity and maximize therapeutic effects.

The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

“…This varied landscape, including cellular and non-cellular components, is termed the TME and encompasses the wide range of cell types and variations in ECM found within and near the tumor. The glioma TME includes both malignant and non-malignant cells -tumor cells, a variety of infiltrating peripheral immune cells, and the cells of the healthy brain such as neurons, neuroglia, and the additional components of the neurovascular unit (NVU), including pericytes and endothelial cells (47)(48)(49)(50). Among the non-malignant cells are local immune cell types, such as microglia and astrocytes, as well as lymphocytes, endothelial, and other cells.…”

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

“…Modern advancements in epigenetics have the potential to develop the individualized patient care needed to address the uniquities of GBM. Most notably, the epigenetic inactivation of MGMT via methylation of its promoter is necessary for temozolomide sensitivity [ 36 , 37 ]. MGMT is a key DNA mismatch repair protein, the absence of which ensures damage from DNA alkylation will result in cell death.…”

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

“…As a result, current investigations are transitioning from single-agent or single-target therapies to treatment modalities with robust mechanisms of action that may overcome disease heterogeneity. Similarly, robust mechanisms of action are required to bypass tumor plasticity and changes in response to unimodal therapies (8,17,(19)(20)(21). Examples of such efforts include cell-based therapies, immunotherapy approaches, and bioengineering strategies such as gene therapy, and excellent overviews of these topics can be found elsewhere (8,9,11,(22)(23)(24).…”