Brain tumours

This Focus issue highlights current research into the unique biology of brain tumours and brain metastasis and how this research might improve therapy of these often devastating diseases.

This Review discusses how advances in our understanding of the immune system within the brain have implications for the successful implementation of immunotherapy to treat brain tumours, despite challenges such as effective delivery, target specificity and intratumour heterogeneity.

This Review discusses the structure and function of the blood–brain barrier (BBB) and how brain tumours and brain metastases compromise BBB integrity. It also discusses the challenges the BBB poses for cancer therapy and how these might be overcome.

This Review discusses recent genomic, epigenomic, transcriptomic and proteomic profiling studies of human medulloblastoma that have advanced our understanding of its disease subgroups. These efforts have provided new insights into the diverse biology of medulloblastomas that will hopefully lead to improved diagnosis and therapy.

This Review discusses altered cellular metabolism in gliomas, with particular regard to the interaction between tumour genotype and the brain microenvironment, and how advances in studying glioma metabolism have contributed to the discovery of potential drug targets.

In this Viewpoint article, we asked four experts to provide their opinions on important aspects of brain metastasis biology, focusing on the unique microenvironment and therapeutic targets in the brain, preclinical models and how studying brain metastases could inform primary brain tumour biology.

Lin et al. and Lambo et al. report in-depth therapeutic screening and genomic profiling, respectively, of two types of aggressive paediatric central nervous system tumours, and both groups identify vulnerabilities of these tumours that might be exploited therapeutically.

Three studies show that synaptic interactions between neurons and glioma cells or cells of breast-cancer-to-brain metastases may promote tumour growth.

O’Connor et al. show that gliosis in the brain contributes to the development of central nervous system lymphomas (CNSLs) through the production of the chemokine CCL19 by astrocytes, which in turn promotes CNSL cell retention in the brain.

Benbenishty et al. find that prophylactic administration of CpG-C, a Toll-like receptor 9 agonist, significantly reduces the development of brain metastasis in preclinical mouse models via the activation of microglial cells that kill and phagocytose the tumour cells.

Parada and colleagues have identified a novel small-molecule inhibitor of oxidative phosphorylation, which exerts cancer-cell-specific toxicity and inhibits glioblastoma growth in mouse models.

Two phase I studies, recently published in Nature, show that the administration of personalized vaccines to newly diagnosed patients with glioblastoma generates tumour-reactive T cells that infiltrate glioblastomas, turning them into ‘hot’ tumours potentially susceptible to further immunotherapy approaches.

Xie et al. have shown that a recently reported DNA modification in mammals, repressive N⁶-methyladenine, is enriched in human glioblastoma and targeting this modification can reduce cancer cell growth by restricting chromatin accessibility at oncogenic loci.

Yao et al. have established that acute lymphoblastic leukaemia cells bypass the need to metastasize via the circulation to the CNS and instead use a direct route migrating along the vascular channels that bridge the bone marrow to the meninges in an α6 integrin-dependent manner.

Vinci et al. provide evidence for subclonal cooperation driving the maintenance of tumour heterogeneity in paediatric high-grade gliomas.

Priego et al. show that a subpopulation of reactive astrocytes expressing signal transducer and activator of transcription 3 (STAT3) is crucial for the development of brain metastases and report positive initial clinical data that inhibiting STAT3 can reduce metastasis.

Single-cell RNA sequencing analysis in paediatric diffuse midline gliomas with histone H3 lysine 27 to methionine mutations indicates that these aggressive tumours contain many stem-like cells and that lineage-based therapeutic targeting might be beneficial.

Two studies have shown that oncolytic virus treatment prior to surgery can prime the tumour immune microenvironment for subsequent immune checkpoint inhibition and lead to better outcomes in preclinical models of breast and brain cancers.

The fusion gene consisting of fibroblast growth factor receptor 3 and transforming acidic coiled-coil-containing protein 3 is oncogenic and present in a small cancer subset. Frattini et al. have identified that this fusion gene drives peroxisomal and mitochondrial biogenesis.