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Single-cell profiling of human prostate cancer and studies in mouse models show that macrophages expressing SPP1 mediate immunotherapeutic resistance through adenosine pathway activation and represent a potential target for future studies.

Elevated levels of interleukin-33 have been associated with poor prognosis in patients with glioma. Here the authors show that glioma-derived IL-33 modulates a pro-tumorigenic immune microenvironment by activating resident and recruiting peripheral innate immune cells.

EZH2 phosphorylation by CDK2 promotes progression of triple-negative breast cancer (TNBC). Here, the authors show that this signaling axis downregulates ERα, and thus combinatorial blockade of CDK2 and EZH2 sensitizes TNBC cells to tamoxifen.

The previous efforts to reprogramme tumour-associated macrophages (TAMs) to M1 phenotype have caused undesired side-effects. Here, the authors report targeted nanocarriers for delivering mRNA encoding M1-polarizing transcription factors to TAMs and show their efficacy in multiple mouse tumour models.

Genome-wide CRISPRi screens for modulators of androgen receptor (AR) protein levels using live-cell quantitative endogenous AR fluorescence reporters identify PTGES3 as a new regulator of AR stability and function in prostate cancer.

Tannishtha Reya and colleagues show that Lis1, a key mediator of asymmetric cell division, is required for blood formation and hematopoietic stem cell function. The authors also show that the directed control of asymmetric division is a critical regulator of malignant hematopoietic development.

Zscan4 is shown to be involved in maintaining telomeres in embryonic stem (ES) cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once within nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis–specific homologous recombination genes. Knocking down Zscan4 shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by eight passages.

In triple-negative breast cancer, the PIM1 kinase is highly expressed, acts to promote tumor cell survival and growth, and increases MYC transcriptional activity.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.

Small-molecule drugs have several advantages that are complementary to, and possibly synergistic with, biologic approaches for anticancer immunotherapy. This Review provides an overview of immunological pathways that can best be targeted with small molecules and discusses how these approaches fit into the armamentarium of immunotherapeutic strategies for cancer.

Aharonov et al. use in vivo genetic approaches to show that ErBB2-mediated YAP activation initiates epithelial–mesenchymal transition-like processes and dedifferentiation of cardiomyocytes to drive heart regeneration.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Translationally controlled tumor protein (TCTP) regulates several cellular processes, including apoptosis, and is overexpressed in several cancer types. Here, the authors report that high levels of TCTP are associated with poor response to anti-PD-L1 and that TCTP targeting increases the efficacy of T cell-mediated anti-tumor therapy.

A scalable barcoding method measures multiple chromatin-associated proteins in single cells.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Biomarker analysis of the phase 3 JAVELIN Bladder 100 trial leads to the development of a multi-parameter model comprising tumor and immune features that might identify patients with advanced urothelial cancer who will benefit from avelumab maintenance therapy.

This Review discusses recent advances in our understanding of the biology of endogenous tissue regeneration in the thymus, highlighting the clinical implications of poor thymic recovery.

The immune response to Zika virus is required to curtail the infection and avoid immunopathology, but may be involved in the associated pathophysiology. Here the authors show that viral persistence and tissue tropism is shaped by an early innate immune response in a pigtail macaque model of infection.

Forkhead transcription factor FoxF2 plays a crucial role in the development of organs derived from primitive gut. Here the authors show that reduction of Foxf2 expression in stromal cells is associated with high grade prostate cancer and that increasing prostatic stromal Foxf2 sensitizes prostate cancer to immune checkpoint blockade.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

Serum antibody responses to sequential homologous booster vaccines derive overwhelmingly from primary cohort B cells at the expense of de novo responses; this ‘primary addiction’ can be overcome by boosting with variant antigens.