Search

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.

Osteosarcomas (OS) are aggressive bone tumors which have no actionable recurrent driver mutations. Here the authors identify aberrant expression of EZHIP in a subset of OS patients as an oncogenic driver, which exhibits vulnerability to epigenetic therapies.

Circulating tumour cells from primary carcinomas may reach the brain and establish metastases. In the brain parenchyma, tumour cells initiate extensive interactions with resident astrocytes, microglia and neurons, forming a niche where tumour cells can thrive. A new study reveals a previously unknown type of astrocyte–tumour cell interaction.

Analysis of medulloblastomas in humans and mice shows that the functional consequences of ZIC1 mutations are exquisitely dependent on the cells of origin that give rise to different subgroups of medulloblastoma.

To address the question of whether a recurrent tumour is genetically similar to the tumour at diagnosis, the evolution of medulloblastoma has been studied in both an in vivo mouse model of clinical tumour therapy as well as in humans with recurrent disease; targeted tumour therapies are usually based on targets present in the tumour at diagnosis but the results from this study indicate that post-treatment recurring tumours (compared with the tumour at diagnosis) have undergone substantial clonal divergence of the initial dominant tumour clone.

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs.

Transposon based screens carried out in mice can identify genes critical for tumourigensis. Here, the authors describe transposon screens in mouse models of breast cancer and highlight a large group of tumour suppressors that could underlie selection for common chromosome arm losses in cancer.

Sequencing data from the developing cerebellum are compared with bulk sequencing data from paediatric tumours, providing insights into their potential origins and suggesting that many cerebellar tumours have their origins early in utero.

A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

Comprehensive genomic profiling of human H3K27M mutant diffuse midline gliomas, combining single-cell RNA sequencing and ATAC sequencing with bulk ChIP sequencing and other data, proposes distinct oligodendrocyte populations as potential cells of origin.

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Highly recurrent hotspot r.3A>G mutations are identified in U1 splicesomal small nuclear RNAs in about 50% of Sonic hedgehog medulloblastomas, which result in disrupted RNA splicing and the activation of oncogenes.

Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models.

Pineoblastoma is a rare pediatric cancer. Here, the authors present inactivation of Rb plus p53 via a WAP-Cre transgene induces metastatic pineoblastoma resembling human disease, and using this model, predict tricyclic antidepressants as a potential therapy for pineoblastoma, supported by their pre-clinical model.

This study shows conserved EAG2 potassium channel function in brain tumorigenesis and metastasis, cooperation of different potassium channels for mitotic volume regulation, and EAG2 enrichment at the trailing edge for local volume regulation and cell motility. The authors identified the FDA-approved drug thioridazine as an EAG2 blocker of potential therapeutic value.

Super enhancers regulate oncogenes and other molecular targets in ependymomas, and identification of these genes provides potential therapeutic targets.

In a mouse model and in human medulloblastoma patients, the metastases in an individual have similar genomic alterations and DNA methylation patterns, but these patterns are highly divergent from those of the primary tumour, indicating that therapies will need to be tailored to fit the molecular alterations present in the primary tumour and/or the metastases.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.