Explore the vast range of titles available.

Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.Deubiquitinating enzymes (DUBs) function in opposition to E3 ubiquitin ligases by removing ubiquitin from substrates to control protein and organelle homeostasis and responses to cellular stimuli. In this Review, Dewson et al. describe the many associations of DUBs with the hallmarks of cancer, with a view to identifying those DUBs most likely to impact cancer-associated phenotypes if targeted with selective inhibition.

Historically, the primary focus of cancer research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen the rapid accumulation of large-scale cancer omics data catalysed by breakthroughs in high-throughput technologies. This fast data growth has given rise to an evolving concept of ‘big data’ in cancer, whose analysis demands large computational resources and can potentially bring novel insights into essential questions. Indeed, the combination of big data, bioinformatics and artificial intelligence has led to notable advances in our basic understanding of cancer biology and to translational advancements. Further advances will require a concerted effort among data scientists, clinicians, biologists and policymakers. Here, we review the current state of the art and future challenges for harnessing big data to advance cancer research and treatment.The increasing size of cancer datasets requires new ways of thinking for analysing and integrating these data. In this Review, Jiang et al. discuss considerations and strategies for wielding ‘big data’ ― large, information-rich datasets ― in basic research and for translational applications such as identifying biomarkers, informing clinical trials and developing new assays and treatments.

Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity.This Review outlines how the profound intertumoural heterogeneity in immune landscapes of tumours is shaped by cancer cell-intrinsic alterations and highlights how the crosstalk between these two continuously evolving systems not only challenges therapy success of immunomodulatory drugs but also provides the basis for new therapeutic strategies to overcome immune evasion.

The genetic information of human cells is stored in the context of chromatin, which is subjected to DNA methylation and various histone modifications. Such a ‘language’ of chromatin modification constitutes a fundamental means of gene and (epi)genome regulation, underlying a myriad of cellular and developmental processes. In recent years, mounting evidence has demonstrated that miswriting, misreading or mis-erasing of the modification language embedded in chromatin represents a common, sometimes early and pivotal, event across a wide range of human cancers, contributing to oncogenesis through the induction of epigenetic, transcriptomic and phenotypic alterations. It is increasingly clear that cancer-related metabolic perturbations and oncohistone mutations also directly impact chromatin modification, thereby promoting cancerous transformation. Phase separation-based deregulation of chromatin modulators and chromatin structure is also emerging to be an important underpinning of tumorigenesis. Understanding the various molecular pathways that underscore a misregulated chromatin language in cancer, together with discovery and development of more effective drugs to target these chromatin-related vulnerabilities, will enhance treatment of human malignancies.Deregulation of chromatin modification underlies a myriad of oncogenic processes. This Review synthesizes the many connections between chromatin modifications and cancer, discussing recent advances and highlighting options for therapeutic targeting.

Specific chemical modifications of biological molecules are an efficient way of regulating molecular function, and a plethora of downstream signalling pathways are influenced by the modification of DNA and proteins. Many of the enzymes responsible for regulating protein and DNA modifications are targets of current cancer therapies. RNA epitranscriptomics, the study of RNA modifications, is the new frontier of this arena. Despite being known since the 1970s, eukaryotic RNA modifications were mostly identified on transfer RNA and ribosomal RNA until the last decade, when they have been identified and characterized on mRNA and various non-coding RNAs. Increasing evidence suggests that RNA modification pathways are also misregulated in human cancers and may be ideal targets of cancer therapy. In this Review we highlight the RNA epitranscriptomic pathways implicated in cancer, describing their biological functions and their connections to the disease.After synthesis, all RNA molecules are subject to covalent modifications. This Review presents the evidence that RNA modification pathways are misregulated in cancer and suggests that they may be ideal targets for cancer therapy.

Meningiomas are the most common primary intracranial tumour in adults 1 . Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas 2 . Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign  NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified. Multi-omics datasets are integrated to generate a unified and clinically informed molecular classification of meningiomas.

The observation and analysis of intra-tumour heterogeneity (ITH), particularly in genomic studies, has advanced our understanding of the evolutionary forces that shape cancer growth and development. However, only a subset of the variation observed in a single tumour will have an impact on cancer evolution, highlighting the need to distinguish between functional and non-functional ITH. Emerging studies highlight a role for the cancer epigenome, transcriptome and immune microenvironment in functional ITH. Here, we consider the importance of both genetic and non-genetic ITH and their role in tumour evolution, and present the rationale for a broad research focus beyond the cancer genome. Systems-biology analytical approaches will be necessary to outline the scale and importance of functional ITH. By allowing a deeper understanding of tumour evolution this will, in time, encourage development of novel therapies and improve outcomes for patients.This Review discusses the role of functional (impacting tumour phenotype) and non-functional intra-tumour heterogeneity (ITH) in cancer evolution, highlighting the importance of considering genetic and non-genetic factors and their impact on patient outcomes.

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance. In their Review article, Fuchs and colleagues discuss how a single or a few mutations in adult cells can lead to invasive cancers without a high mutational burden, demonstrating that non-genetic factors induce the epigenetic changes necessary for tumorigenesis.

Cancer represents an evolutionary process through which growing malignant populations genetically diversify, leading to tumour progression, relapse and resistance to therapy. In addition to genetic diversity, the cell-to-cell variation that fuels evolutionary selection also manifests in cellular states, epigenetic profiles, spatial distributions and interactions with the microenvironment. Therefore, the study of cancer requires the integration of multiple heritable dimensions at the resolution of the single cell — the atomic unit of somatic evolution. In this Review, we discuss emerging analytic and experimental technologies for single-cell multi-omics that enable the capture and integration of multiple data modalities to inform the study of cancer evolution. These data show that cancer results from a complex interplay between genetic and non-genetic determinants of somatic evolution.Both genetic and non-genetic factors underlie the intratumoural heterogeneity that fuels cancer evolution. This Review discusses the application of single-cell multi-omics technologies to the study of cancer evolution, which capture and integrate the different layers of heritable information and reveal their complex interplay.

Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease.