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Tumours build their niche p.292

It emerges that tumour cells can give rise to non-dividing cells that form part of the supporting microenvironment known as the niche. These niche cells secrete proteins that drive tumour growth and progression. See Letters p.355 & p.360

Meritxell Huch & Emma L. Rawlins

doi: 10.1038/nature22494

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Quantum theory verified by experiment p.293

Systems of quantum objects can be characterized by the correlations between the objects. A technique that precisely measures even the most delicate of these correlations allows models of quantum systems to be tested. See Letter p.323

Ian B. Spielman

doi: 10.1038/545293a

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Tools to eliminate senescent cells p.294

Ageing and many diseases are partly driven by the accumulation of damaged cells that no longer divide. It emerges that these senescent cells can be eradicated in mice using a drug that interferes with the activity of the protein FOXO4.

Manuel Serrano

doi: 10.1038/nature22493

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Half a century of robust climate models p.296

A classic paper in 1967 reported key advances in climate modelling that enabled a convincing quantification of the global-warming effects of carbon dioxide — laying foundations for the models that underpin climate research today.

Piers Forster

doi: 10.1038/545296a

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Occasional errors can benefit coordination p.297

The chances of solving a problem that involves coordination between people are increased by introducing robotic players that sometimes make mistakes. This finding has implications for real-world coordination problems. See Letter p.370

Simon Gächter

doi: 10.1038/545297a

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Articles

Predictive compound accumulation rules yield a broad-spectrum antibiotic p.299

The authors use computational modelling and a set of chemically synthesized compounds to define the physicochemical properties required for small-molecule accumulation in Gram-negative bacteria.

Michelle F. Richter, Bryon S. Drown, Andrew P. Riley, Alfredo Garcia, Tomohiro Shirai, Riley L. Svec & Paul J. Hergenrother

doi: 10.1038/nature22308

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Endothelial TLR4 and the microbiome drive cerebral cavernous malformations p.305

Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans.

Alan T. Tang, Jaesung P. Choi, Jonathan J. Kotzin, Yiqing Yang, Courtney C. Hong, Nicholas Hobson, Romuald Girard, Hussein A. Zeineddine, Rhonda Lightle, Thomas Moore + et al.

doi: 10.1038/nature22075

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Discovery of nitrate–CPK–NLP signalling in central nutrient–growth networks p.311

In response to nitrate, Ca2+-sensor protein kinases (CPKs) act as master regulators to coordinate downstream signalling responses that are essential for shoot growth and root establishment in Arabidopsis.

Kun-hsiang Liu, Yajie Niu, Mineko Konishi, Yue Wu, Hao Du, Hoo Sun Chung, Lei Li, Marie Boudsocq, Matthew McCormack, Shugo Maekawa + et al.

doi: 10.1038/nature22077

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Selectivity determinants of GPCR–G-protein binding p.317

The identification of the positions and patterns of amino acids that form the selectivity determinants for the entire human G-protein and G-protein-coupled receptor signalling system.

Tilman Flock, Alexander S. Hauser, Nadia Lund, David E. Gloriam, Santhanam Balaji & M. Madan Babu

doi: 10.1038/nature22070

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Letters

Experimental characterization of a quantum many-body system via higher-order correlations p.323

Experimental measurements of higher-order correlation functions in many-body systems provide insight into a non-trivial quantum field theory and how it can be implemented in a cold-atom quantum simulation.

Thomas Schweigler, Valentin Kasper, Sebastian Erne, Igor Mazets, Bernhard Rauer, Federica Cataldini, Tim Langen, Thomas Gasenzer, Jürgen Berges & Jörg Schmiedmayer

doi: 10.1038/nature22310

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Topological defects control collective dynamics in neural progenitor cell cultures p.327

Cultured stem cells have become a standard platform not only for regenerative medicine and developmental biology but also for biophysical studies. Yet, the characterization of cultured stem cells at the level of morphology and of the macroscopic patterns resulting from cell-to-cell interactions remains largely qualitative. Here we report on the collective dynamics of cultured murine neural progenitor cells (NPCs), which are multipotent stem cells that give rise to cells in the central nervous system. At low densities, NPCs moved randomly in an amoeba-like fashion. However, NPCs at high density elongated and aligned their shapes with one another, gliding at relatively high velocities. Although the direction of motion of individual cells reversed stochastically along the axes of alignment, the cells were capable of forming an aligned pattern up to length scales similar to that of the migratory stream observed in the adult brain. The two-dimensional order of alignment within the culture showed a liquid-crystalline pattern containing interspersed topological defects with winding numbers of +1/2 and −1/2 (half-integer due to the nematic feature that arises from the head–tail symmetry of cell-to-cell interaction). We identified rapid cell accumulation at +1/2 defects and the formation of three-dimensional mounds. Imaging at the single-cell level around the defects allowed us to quantify the velocity field and the evolving cell density; cells not only concentrate at +1/2 defects, but also escape from −1/2 defects. We propose a generic mechanism for the instability in cell density around the defects that arises from the interplay between the anisotropic friction and the active force field.

Kyogo Kawaguchi, Ryoichiro Kageyama & Masaki Sano

doi: 10.1038/nature22321

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Experimental evidence that thrust earthquake ruptures might open faults p.336

Earthquake rupture experiments and mathematical modelling reveal the existence of a torquing mechanism of thrust fault ruptures near the free surface that causes them to dynamically unclamp, open and slip large distances.

Vahe Gabuchian, Ares J. Rosakis, Harsha S. Bhat, Raúl Madariaga & Hiroo Kanamori

doi: 10.1038/nature22045

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Whole-brain serial-section electron microscopy in larval zebrafish p.345

A complete larval zebrafish brain is examined and its myelinated axons reconstructed using serial-section electron microscopy, revealing remarkable symmetry and providing a valuable resource.

David Grant Colburn Hildebrand, Marcelo Cicconet, Russel Miguel Torres, Woohyuk Choi, Tran Minh Quan, Jungmin Moon, Arthur Willis Wetzel, Andrew Scott Champion, Brett Jesse Graham, Owen Randlett + et al.

doi: 10.1038/nature22356

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Floor-plate-derived netrin-1 is dispensable for commissural axon guidance p.350

Preventing netrin secretion from floor-plate cells at the midline does not disrupt axonal guidance; commissural axons develop normally and the data suggest that netrin may influence axons locally by promoting growth cone adhesion.

Chloé Dominici, Juan Antonio Moreno-Bravo, Sergi Roig Puiggros, Quentin Rappeneau, Nicolas Rama, Pauline Vieugue, Agns Bernet, Patrick Mehlen & Alain Chédotal

doi: 10.1038/nature22331

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A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma p.355

The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.

Tuomas Tammela, Francisco J. Sanchez-Rivera, Naniye Malli Cetinbas, Katherine Wu, Nikhil S. Joshi, Katja Helenius, Yoona Park, Roxana Azimi, Natanya R. Kerper, R. Alexander Wesselhoeft + et al.

doi: 10.1038/nature22334

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Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer p.360

In a mouse model of small-cell lung cancer and in human tumours, activation of the Notch pathway can lead to a cell fate switch of neuroendocrine cells to less proliferative non-neuroendocrine cells, generating intratumoural heterogeneity.

Jing Shan Lim, Alvaro Ibaseta, Marcus M. Fischer, Belinda Cancilla, Gilbert O’Young, Sandra Cristea, Vincent C. Luca, Dian Yang, Nadine S. Jahchan, Cécile Hamard + et al.

doi: 10.1038/nature22323

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TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling p.365

The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients and growth factors, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling. Although both mTOR and GβL (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11, 12, 13, 14, 15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of GβL dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of GβL, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12, 13, 14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from GβL to promote GβL interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in GβL, by either K305R/K313R mutations or a melanoma-associated GβL(ΔW297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a GβL-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.

Bin Wang, Zuliang Jie, Donghyun Joo, Alban Ordureau, Pengda Liu, Wenjian Gan, Jianping Guo, Jinfang Zhang, Brian J. North, Xiangpeng Dai + et al.

doi: 10.1038/nature22344

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