Can Sarm1 Inhibition Inhibit Glioblastoma Multiforme Progression and Preserve Neuronal Function?

Can We Identify a Therapeutic Target for Early-Stage Glioblastoma Therapy?

The advanced stages of glioblastoma multiforme (GBM) - a highly aggressive and therapy-resistant malignant primary brain tumor (McKinnon et al. and Qazi et al.) have been studied in great detail; however, we still lack effective treatment options for late-stage tumors (when debilitating associated symptoms typically first appear), mainly due to the elevated levels of molecular and cellular heterogeneity, extensive infiltration, and immune suppression. Perhaps more importantly, we also lack a deeper understanding of the events underlying the early and perhaps more responsive to treatment stages of GBM development and the mechanisms that drive subsequent progression to the advanced, therapy-resistant form of the disease. Of note, a large body of work now suggests that GBM initiation includes a latent preclinical phase that progresses to advanced disease under the influence of cooperating tumor-extrinsic signals.

A team of researchers led by Ciaran S. Hill and Simona Parrinello (University College London) reported their most recent findings in a new study that combined tissue analysis in somatic mouse models and spatial transcriptomics in patient-derived xenograft models/human tissue to examine mechanisms active during early-stage GBM that promote disease progression. Fascinatingly, the authors now provide evidence that axonal injury in the white matter of the brain induced by the expansion of early tumor cells represents a crucial driver of GBM progression in a recent Nature: Clements, Tang, Florjanic Baronik, and Simpson Ragdale et al.

A more detailed analysis of single tumor and central nervous system cells that take part in this tumor-promoting mechanism may provide deeper insight; could the additional integration of simultaneous profiling of transcriptomics and epigenetics in single cells afforded by applying Paired-Tag technology from Epigenome Technologies further our understanding? Paired-Tag technology from Epigenome Technologies generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with comparable efficiency to single-nucleus RNA-seq/ChIP-seq assays while avoiding the need for cell sorting. Could the implementation of this integrated approach provide additional therapeutic targets for the treatment of early-stage GBM?

The Nerve! How Axonal Injury Promotes Glioblastoma Development

The authors first studied disease-relevant somatic mouse models of GBM (Garcia-Diaz et al. and Clements et al.) (where neural stem cells from the subventricular zone become transformed through tumor suppressor inactivation), where they found proof that alterations induced by the production of early tumor cells within the white matter microenvironment may drive GBM progression from a latent to advanced disease stage. Next, spatial transcriptomics analysis of samples from genetically heterogeneous patient-derived xenograft models collected at early or terminal disease stages suggested that developing GBM induces white matter injury, beginning at early disease stages and continuing throughout tumorigenesis. The subsequent analysis of mouse reads in white matter over time, comparing control brains with early and terminal tumors, revealed that the analysis of tumor density (a proxy for progression in terminal tumors) highlighted a particular vulnerability of axons within white matter to tumor-induced damage and axonal degeneration at low tumor cell densities. These findings raised the possibility of axonal injury as a critically important driver of GBM progression. Subsequent studies indicated that compression and mechanical stress caused by infiltrating tumor cells contributed to axonal loss in early tumors; furthermore, the accompanying progressive increase in neuroinflammation also suggested an important role for astrocytes and microglia in driving early GBM progression.

Mechanical axonal injury can lead to downstream axonal degeneration (impairing function and/or prompting neural death; Hill et al. and Johnson et al.) via Wallerian degeneration (Hill et al. and Coleman & Hoke) - an active program of anterograde axonal degeneration mediated by the Sarm1 protein in mice (Osterloh et al. and Essuman et al.). Fascinatingly, the authors revealed that tumors induced in Sarm1-null mice displayed reduced axonal loss in the white matter, suggesting Wallerian degeneration as the major mediator of axonal degeneration in early GBM development. Additional experiments in Sarm1-null mice subjected to axonal transection injury, as a well-established experimental paradigm for the induction of Wallerian degeneration, revealed that axonal injury and the subsequent Wallerian degeneration increase neuroinflammation and promote GBM progression to advanced disease, and that Sarm1 inactivation rescued this process.

The final part of this fascinating study focused on how the inhibition of Sarm1 may delay GBM progression. GBM tumors induced in wild-type mice displayed a greater level of aggressive neuropathological features when compared to tumors in Sarm1-null mice, suggesting that the absence of Wallerian degeneration prompted the appearance of less advanced tumors. Single-cell RNA-sequencing analysis also supported the fact that inhibition of Sarm1 significantly slowed tumor progression to densely cellular, angiogenic, and immune-suppressive lesions and inhibited the accompanying transition of tumor cells to a mesenchymal-like/injured state (Ravi et al. and Hara et al.); instead, Sarm1 inhibition prompted the development of more diffuse, less inflamed tumors that closely mirrored normal neurodevelopmental lineages. Finally, and perhaps most encouragingly, the team revealed that Sarm1 loss in GBM model mice resulted in a significant extension of survival and

Sarm1 Inhibition Inhibiting Glioblastoma Progression and Preserving Neuronal Function

While we understood that neuronal activity can impact GBM proliferation, invasion, and therapy resistance (Winkler et al.), this exciting new study suggests a neuroncancer interaction - GBM progression induced by injured axons as profoundly important. Furthermore, these data suggest that targeting the tumor-induced injured microenvironment by pharmacologically inhibiting Sarm1, as a critical regulator of Wallerian degeneration, may suppress disease progression to advanced stages while preserving neurological function, thereby improving the quality of life for affected patients.

The additional integration of simultaneous profiling of transcriptomics and epigenetics in single cells, afforded by applying Paired-Tag technology from Epigenome Technologies, could provide a more detailed analysis of single tumor and central nervous system cells that take part in this tumor-promoting mechanism and reveal additional therapeutic targets for the treatment of early-stage GBM.