Volume 540 Number 7634

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Pathways of parallel progression p.528

Two studies in mice identify mechanisms by which tumour cells disseminate in very early breast cancer. Both show that these cells colonize distant tissues more efficiently than their later counterparts. See Article p.552 & Letter p.588

doi: 10.1038/nature21104

Unexplored territory for self-assembly p.529

Cage-like structures can self-assemble from suitable metal ions and organic linkers, but the size of the assemblies was limited. The surprise discovery of a new series of cages opens up fresh horizons for self-assembly. See Letter p.563

doi: 10.1038/540529a

A turbulent path to plaque formation p.531

Plaque deposits often occur in curved arterial regions with turbulent blood flow. Endothelial cells have been found to respond to blood flow through a previously unidentified signalling pathway that affects plaque build-up. See Letter p.579

doi: 10.1038/nature20489

Sharks shift their spine into high gear p.532

It emerges that a dogfish shark's spine becomes stiffer as the fish swims faster, enabling the animal to swim efficiently at different speeds. The finding could also provide inspiration for the design of robotic biomaterials.

doi: 10.1038/nature21102

Quantum mechanics in a spin p.534

Quantum spin liquids are exotic states of matter first predicted more than 40 years ago. An inorganic material has properties consistent with these predictions, revealing details about the nature of quantum matter. See Letter p.559

doi: 10.1038/540534a

Articles

Redefining the invertebrate RNA virosphere p.539

Profiling the total RNA of 220 invertebrate species leads to the discovery of almost 1,500 new species of RNA virus, revealing that the RNA virosphere is much more diverse than was previously thought.

doi: 10.1038/nature20167

Early dissemination seeds metastasis in breast cancer p.552

Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination.

doi: 10.1038/nature20785

Letters

Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow p.579

The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1), effectors of the Hippo pathway, have been identified as mediators for mechanical stimuli. However, the role of YAP/TAZ in haemodynamics-induced mechanotransduction and pathogenesis of atherosclerosis remains unclear. Here we show that endothelial YAP/TAZ activity is regulated by different patterns of blood flow, and YAP/TAZ inhibition suppresses inflammation and retards atherogenesis. Atheroprone-disturbed flow increases whereas atheroprotective unidirectional shear stress inhibits YAP/TAZ activity. Unidirectional shear stress activates integrin and promotes integrin–Gα13 interaction, leading to RhoA inhibition and YAP phosphorylation and suppression. YAP/TAZ inhibition suppresses JNK signalling and downregulates pro-inflammatory genes expression, thereby reducing monocyte attachment and infiltration. In vivo endothelial-specific YAP overexpression exacerbates, while CRISPR/Cas9-mediated Yap knockdown in endothelium retards, plaque formation in ApoE/ mice. We also show several existing anti-atherosclerotic agents such as statins inhibit YAP/TAZ transactivation. On the other hand, simvastatin fails to suppress constitutively active YAP/TAZ-induced pro-inflammatory gene expression in endothelial cells, indicating that YAP/TAZ inhibition could contribute to the anti-inflammatory effect of simvastatin. Furthermore, activation of integrin by oral administration of MnCl2 reduces plaque formation. Taken together, our results indicate that integrin–Gα13–RhoA–YAP pathway holds promise as a novel drug target against atherosclerosis.

doi: 10.1038/nature20602

Mechanism of early dissemination and metastasis in Her2+ mammary cancer p.588

Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours. However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2+p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC precursors invaded locally, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent epithelial–mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1hiE-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.

doi: 10.1038/nature20609

Structure of RNA polymerase I transcribing ribosomal DNA genes p.607

Structures of budding yeast RNA polymerase I in a catalytically active conformation are presented and confirmed by visualizing processive transcription along ribosomal DNA genes; they support a general model for transcription elongation in which contracted and expanded polymerase conformations are associated with active and inactive states, respectively.

doi: 10.1038/nature20561