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Cynthia Hawkins, Oren Becher and colleagues report the identification of recurrent mutations in ACVR1 in 20% of diffuse intrinsic pontine gliomas. Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2 . Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Chris Jones, Jacques Grill and colleagues report the identification of recurrent activating mutations in ACVR1 in diffuse intrinsic pontine gliomas. Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9–12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors 1 . We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) 2 and have been shown to constitutively activate the BMP–TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

Brainstem tumors exert profound effects on cortical organization and functionality across the whole brain. However, the precise implications of changes in cortical thickness (CTh) for patient stratification and prognostic assessment remain unclear. Our study seeks to address these gaps and provide clearer insights into the distant impact of brainstem tumors. This study involved 124 pediatric patients with brainstem tumors and 849 healthy controls. Using CAT12 segmentation on 3D T1-weighted MRI scans and Gaussian process regression modeling, we established a normative CTh model from healthy data. CTh deviations of patients were quantified and clustered, revealing two distinct subtypes: Subtype 1 with extremely positive deviations and Subtype 2 with extremely negative deviations, correlating with better survival. Kaplan-Meier analysis confirmed significant survival differences between these subtypes. Additionally, a greater number of brain regions with positive CTh deviations was found to correlate with larger tumor volumes. These findings suggest that CTh deviation is a non-invasive imaging marker, facilitating patient subtyping and survival prediction. These insights equip clinicians to tailor treatment plans and establishes a valuable precision medical tool for clinical evaluation and monitoring.

Brainstem gliomas are highly heterogeneous tumors both in their clinical manifestation and in their pathology. Despite significant advances in the surgery for brainstem gliomas many aspects of this pathology are still unclear. To evaluate the clinical, radiological and surgical outcome of 40 focal 'intrinsic' brainstem gliomas and propose a surgical strategy-oriented classification. A total of 40 focal 'intrinsic' (\"expanding variety\") tumors have been operated over a period of 8.5-years (January 1998-June 2007). Our criteria included patients with (1) well-defined gadolinium enhancing tumor; (2) relatively long duration of symptoms (> six months) and (3) good neurological functional status and independent for all activities of daily living. The cutoff size of 2 cm was not rigidly adhered to. The 'intrinsic' brainstem tumors were classified into three types: Expanding, diffuse infiltrative and pure ventral varieties. Only patients with expanding variety of brainstem gliomas were subjected to surgery, mean age 19.2 years (range 4-55 years) and male to female ration mean: 3:2). The tumor location included pons (n=19), midbrain (n=13) and medulla (n=8). Surgical approaches included midline suboccipital (n=28), retromastoid (n=7), subtemporal (n=3) and supracerebellar-infratentorial (n=2). Thirty-two cases with 'diffuse infiltrative' and 'pure ventral' variety were given radiotherapy only. Histology pathology revealed pilocytic variety (n=10), Grade II (n=17) and Grade III (n=13). There was one death in the surgical series (due to aspiration). Complications included meningitis (n=2), wound infection (n=1), chest infection (n=5) and transient mutism (n=1). Follow-up ranged from 3-68 months. Overall, 36 improved /remained same and three worsened in their clinical status at the time of discharge. The surgical management of intrinsic brainstem tumors presents a surgical challenge; radical excision yielded a good outcome in the majority of cases. The authors propose a classification system for 'intrinsic' brainstem tumors for defining surgical strategy.

Single-cell RNA sequencing identifies a common origin for specific types of human glioma brain tumors. Glioma brain tumors that carry mutant copies of the IDH gene can be subdivided into two major classes. However, the development of and differences between these two classes are not well characterized. Venteicher et al. coupled bulk sequencing and publicly available data with single-cell RNA sequencing data on glioma patient tissue samples. They identified a common lineage program that is shared between glioma subtypes. This suggests that the observed differences between the two glioma classes originate from lineage-specific genetic changes and the tumor microenvironment. Science , this issue p. eaai8478 Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)–mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin + stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood. 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.

In spite of relentless efforts to devise new treatment strategies, primary glioblastomas invariably recur as aggressive, therapy-resistant relapses and patients rapidly succumb to these tumors. Many therapeutic agents are first tested in clinical trials involving recurrent glioblastomas. Remarkably, however, fundamental knowledge on the biology of recurrent glioblastoma is just slowly emerging. Here, we review current knowledge on recurrent glioblastoma and ask whether and how therapies change intra-tumor heterogeneity, molecular traits and growth pattern of glioblastoma, and to which extent this information can be exploited for therapeutic decision-making. We conclude that the ability to characterize and predict therapy-induced changes in recurrent glioblastoma will determine, whether, one day, glioblastoma can be contained in a state of chronic disease.

The 4th edition of the World Health Organization (WHO) classification of endocrine tumors has been recently released. In this new edition, major changes are recommended in several areas of the classification of tumors of the anterior pituitary gland (adenophypophysis). The scope of the present manuscript is to summarize these recommended changes, emphasizing a few significant topics. These changes include the following: (1) a novel approach for classifying pituitary neuroendocrine tumors according to pituitary adenohypophyseal cell lineages; (2) changes to the histological grading of pituitary neuroendocrine tumors with the elimination of the term “atypical adenoma;” and (3) introduction of new entities like the pituitary blastoma and re-definition of old entities like the null-cell adenoma. This new classification is very practical and mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemical markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki-67 labeling index, and tumor invasion is strongly recommended on individual case basis to identify clinically aggressive adenomas. In addition, the classification offers the treating clinical team information on tumor prognosis by identifying specific variants of adenomas associated with an elevated risk for recurrence. Changes in the classification of non-neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. These changes endorse those previously published in the 2016 WHO classification of CNS tumors. Other tumors arising in the sellar region are also reviewed in detail including craniopharyngiomas, mesenchymal and stromal tumors, germ cell tumors, and hematopoietic tumors. It is hoped that the 2017 WHO classification of pituitary tumors will establish more biologically and clinically uniform groups of tumors, make it possible for practicing pathologists to better diagnose these tumors, and contribute to our understanding of clinical outcomes for patients harboring pituitary tumors.

Glioblastomas are the most prevalent primary brain tumors and are associated with a dramatically poor prognosis. Despite an intensive treatment approach, including maximal surgical tumor removal followed by radio- and chemotherapy, the median survival for glioblastoma patients has remained around 18 months for decades. Glioblastoma is distinguished by its highly complex mechanisms of immune evasion and pronounced heterogeneity. This variability is apparent both within the tumor itself, which can exhibit multiple phenotypes simultaneously, and in its surrounding microenvironment. Another key feature of glioblastoma is its “cold” microenvironment, characterized by robust immunosuppression. Recent advances in single-cell RNA sequencing have uncovered new promising insights, revealing previously unrecognized aspects of this tumor. In this review, we consolidate current knowledge on glioblastoma cells and its microenvironment, with an emphasis on their biological properties and unique patterns of molecular communication through signaling pathways. The evidence underscores the critical need for personalized poly-immunotherapy and other approaches to overcome the plasticity of glioblastoma stem cells. Analyzing the tumor microenvironment of individual patients using single-cell transcriptomics and implementing a customized immunotherapeutic strategy could potentially improve survival outcomes for those facing this formidable disease.

Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.The Notch pathway plays multiple complex roles in cancer, exerting oncogenic or tumour-suppressive actions depending on the context. Here Miele and colleagues provide an overview of current understanding of the functions of Notch in cancer, highlighting key implications for the development of Notch-targeting therapeutics. Agents in clinical development and emerging therapeutic strategies are highlighted.