Volume 554 Number 7693

Editorials

Adolescence research must grow up p.403

Young people get a raw deal from society. Targeted study and approaches as part of a new global effort are urgently needed to help them.

doi: 10.1038/d41586-018-02185-w

News

News Features

News & Views

Pruning hypothesis comes of age p.438

The idea that disrupted pruning of neuronal connections in the brain during adolescence is a cause of schizophrenia was proposed in 1983. This proved prescient, as subsequent imaging, genetic and molecular research has shown.

doi: 10.1038/d41586-018-02053-7

Molecules pressured to react p.468

Crystals have been made that undergo reactions when compressed. Computational simulations of these processes provide much-needed atomic-level insight into the mechanisms of mechanically induced reactions.

doi: 10.1038/d41586-018-02047-5

Force-activated ion channels in close-up p.469

Piezo proteins allow cells to sense forces by letting ions pass through the cell membrane in response to mechanical stimuli. Three structures of a Piezo protein shed light on how this crucial process works.

doi: 10.1038/d41586-018-01631-z

An inflammatory transcriptional switch p.470

The mouse pancreas adopts a pre-inflammatory state in response to a chemical injury or the loss of one copy of the gene Nr5a2. This state might predispose mice, and possibly humans, to pancreatitis and pancreatic cancer.

doi: 10.1038/d41586-018-01262-4

Neurons mimicked by electronics p.472

Electronic devices can currently emulate only basic functions of biological neurons. Devices called memtransistors could overcome this limitation and give rise to improvements in artificial-intelligence systems.

doi: 10.1038/d41586-018-02025-x

Perspectives

Analysis

Articles

Structure of the mechanically activated ion channel Piezo1 p.481

The cryo-electron microscopy structure of full-length mouse Piezo1 reveals six Piezo repeats, and 26 transmembrane helices per protomer, and shows that a kinked helical beam and anchor domain link the Piezo repeats to the pore and control gating allosterically.

doi: 10.1038/nature25453

Structure and mechanogating mechanism of the Piezo1 channel p.487

The electron cryo-microscopy structure of full-length mouse Piezo1 reveals unique topological features such as the repetitive transmembrane helical units that constitute the highly curved transmembrane region, and identifies regions and single residues that are crucial for the mechanical activation of the channel.

doi: 10.1038/nature25743

Letters

Global patterns of tropical forest fragmentation p.519

Satellite data and modelling reveal that tropical forest fragments have similar size distributions across continents, and that forest fragmentation is close to a critical point, beyond which fragment numbers will strongly increase.

doi: 10.1038/nature25508

Peptidoglycan synthesis drives an FtsZ-treadmilling-independent step of cytokinesis p.528

Peptidoglycan is the main component of the bacterial wall and protects cells from the mechanical stress that results from high intracellular turgor. Peptidoglycan biosynthesis is very similar in all bacteria; bacterial shapes are therefore mainly determined by the spatial and temporal regulation of peptidoglycan synthesis rather than by the chemical composition of peptidoglycan. The form of rod-shaped bacteria, such as Bacillus subtilis or Escherichia coli, is generated by the action of two peptidoglycan synthesis machineries that act at the septum and at the lateral wall in processes coordinated by the cytoskeletal proteins FtsZ and MreB, respectively. The tubulin homologue FtsZ is the first protein recruited to the division site, where it assembles in filaments—forming the Z ring—that undergo treadmilling and recruit later divisome proteins. The rate of treadmilling in B. subtilis controls the rates of both peptidoglycan synthesis and cell division. The actin homologue MreB forms discrete patches that move circumferentially around the cell in tracks perpendicular to the long axis of the cell, and organize the insertion of new cell wall during elongation. Cocci such as Staphylococcus aureus possess only one type of peptidoglycan synthesis machinery, which is diverted from the cell periphery to the septum in preparation for division. The molecular cue that coordinates this transition has remained elusive. Here we investigate the localization of S. aureus peptidoglycan biosynthesis proteins and show that the recruitment of the putative lipid II flippase MurJ to the septum, by the DivIB–DivIC–FtsL complex, drives peptidoglycan incorporation to the midcell. MurJ recruitment corresponds to a turning point in cytokinesis, which is slow and dependent on FtsZ treadmilling before MurJ arrival but becomes faster and independent of FtsZ treadmilling after peptidoglycan synthesis activity is directed to the septum, where it provides additional force for cell envelope constriction.

doi: 10.1038/nature25506

TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis p.538

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

doi: 10.1038/nature25492

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells p.544

Therapeutic antibodies that block the programmed death-1 (PD-1)–programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.

doi: 10.1038/nature25501