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2019 marks twenty years since the launch of Nature Cell Biology. To celebrate our 20th anniversary we present a Focus of specially commissioned Review and Perspective articles that discuss topics across the diverse areas covered by the journal. These pieces are accompanied by a Collection of research articles published in Nature Cell Biology over the last two decades. Although they are not intended to be comprehensive, these commissioned pieces and research articles highlight the rich history and diverse scope of the journal.
This year marks the twentieth anniversary of the launch of Nature Cell Biology. We take this opportunity to reflect on the progress in cell biological research and the evolution of our journal, and to celebrate the start of our third decade with a special Focus on 20 years of cell biology.
In this Perspective, Dekoninck and Blanpain describe the characteristics of skin epithelial stem cells, their heterogeneity, clonal dynamics, crosstalk with other cells and remarkable plasticity during wound healing.
This Review describes non-redundant functions of the core transcription factors that mediate the epithelial–mesenchymal transition, and discusses the conflicting results regarding their roles in this process.
Joungmok Kim and Kunliang Guan review the landmark discoveries in the mTOR field from the identification of rapamycin to the characterization of mTOR complex components, with an emphasis on the key players mediating amino acid signals to mTOR.
In this Review, Horng and colleagues cover the emerging roles of cellular metabolism in guiding immune cell activation and cell fate decisions, and discuss how differential metabolic regulation allows for context specificity.
Moreno-Layseca et al. discuss how integrins, key receptors that mediate cell adhesion to the extracellular matrix, are endocytosed and recycled to the cell surface to modulate cell and tissue behaviour.
Valencia and Kadoch review diverse functions of DNA and histone modifying proteins, and chromatin remodelling complexes in cancer, and discuss how these may be favourably leveraged for therapeutic development.
In this Review Article, Chunduri and Storchová discuss how aneuploidy, often seen in cancer cells, affects gene expression, proliferation, proteotoxic stress and genomic stability, and how these changes relate to those in cancer.
In this Review, Lawrence and Zoncu discuss the central role of the lysosome in cellular metabolism, including in macromolecular catabolism and nutrient recycling, and organelle crosstalk. They highlight the emerging function of the lysosome as a centre for nutrient sensing and metabolic signal transduction.
Lyden and colleagues use asymmetric flow field-flow fractionation to classify nanoparticles derived from cell lines and human samples, including previously uncharacterized large, Exo-L and small, Exo-S, exosome subsets.
Glück et al. find that the DNA-sensing component cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments produced in senescent cells leading to STING-mediated production of SASPs, which promotes paracrine senescence.
Integrins and talin are parts of a ‘molecular clutch’ that mechanically links the actin cytoskeleton to the extracellular matrix. Elosegui-Artola et al. now reveal a tunable rigidity threshold, above which talin unfolds to mediate force transduction.
Medina, Ballabio and colleagues report that calcium release from the lysosome stimulates calcineurin, which dephosphorylates and activates TFEB. These findings reveal a central role for calcium signalling in autophagy and lysosome homeostasis.
A property of oncogene-induced senescence (OIS) is the induction of a secretory phenotype, termed the senescence-associated secretome (SASP). Gil and colleagues now provide evidence that senescence can be transmitted in a paracrine manner, by showing that induction of the SASP in cells undergoing OIS by inflammasome-mediated interleukin-1 signalling can promote senescence of normal neighbouring cells.
D’Adda di Fagagna and colleagues observe that, after genotoxic treatment of cells and mice, unrepaired DNA-damage foci and DNA-damage signalling persist at telomeres. They show that introducing the telomeric protein TRF2 near a double-strand break elsewhere on the chromosomes prevents repair. Unrepaired foci are also observed at telomeres of ageing animals, suggesting a role for TRF2 in senescence establishment.
In mammalian cells, long-range vesicular transport is thought to occur via microtubule tracks. However, Schuh reports the existence of an actin-based pathway for long-range trafficking in mouse oocytes by showing that Rab11a-positive vesicles are decorated with actin-nucleating formin proteins. She finds that these proteins assemble actin networks that guide vesicles to the cell surface.
A molecular mechanism that links the mTOR and autophagy pathways is now revealed. Depending on nutrient availability, the AMPK and mTOR kinases differentially phosphorylate the autophagy-initiating kinase Ulk1 to regulate its activity.
As focal adhesions mature in response to mechanical tension and contractility, their protein composition changes. A proteomics analysis of focal adhesions following changes in myosin II activity highlights a role for the Rac guanine exchange factor β-Pix in promoting cell migration and nascent focal adhesion turnover, thereby preventing their maturation.
Impaired turnover of the autophagy substrate p62 leads to liver injury. p62 inhibits the ubiquitin ligase Keap1, leading to stabilization of the transcription factor Nrf2. High levels of p62 in autophagy deficient animals leads to unusually high expression of Nrf2 targets genes and results in liver injury.
The E3 ubiquitin ligase Parkin mediates the clearance of depolarized mitochondria through the autophagy pathway. PINK1 kinase activity is required for Parkin translocation to depolarized mitochondria where Parkin generates polyubiquitin chains on the voltage-dependent anion channel (VDAC1) to recruit the autophagic adaptor p62/SQSTM1.
Persistent DNA damage activation and oncogene-induced senescence stimulate secretion of the inflammatory cytokine IL-6, which is mediated by the damage-response pathway including ATM, NBS1 and CHK2. Tumours with an activated DNA damage response show elevated IL-6 and invasiveness.
Exosome biogenesis is poorly understood. The small GTPases Rab27a and Rab27b and their effectors, Slp4 and Slac2b, control exosome secretion at different steps by regulating the peripheral localization, retention and docking of exosomal precursors, the multivesicular endosomes.
Velten et al. use single-cell transcriptomics and functional data to map the early lineage commitment of human haematopoietic stem cells as a continuous process of cells passing through transitory states rather than demarcating discrete progenitors.
Chen et al. generate lung bud organoids from human pluripotent stem cells that recapitulate early lung development, such as branching airway formation and early alveolar structures, which could potentially be used to model lung disease.
Park et al. study individual cell dynamics during mouse wound re-epithelialization in real time and reveal a finely orchestrated interplay between epidermal migration, directional division and differentiation.
Henninger et al. analyse the early clonal events that underlie haematopoiesis and establish the number of stem cell clones that arise from the ventral dorsal aorta to maintain lifelong blood production.
Zernicka-Goetz and colleagues report an in vitro culture system that recapitulates hallmarks of human embryo morphogenesis before gastrulation, including formation of the pro-amniotic cavity and appearance of the prospective yolk sac.
By comparing the metabolomes, transcriptomes and epigenomes of human pluripotent stem cell lines, Sperber et al. show that interplay between the metabolome and histone modifications drives the metabolic switch from naive to primed pluripotency.
Differentiation of pluripotent cells into renal lineages has had limited success so far. Melissa Little and colleagues have used defined medium conditions that induce posterior primitive streak and intermediate mesoderm using growth factors used during normal embryogenesis. This results in the synchronous induction of both components of the kidney, the ureteric bud and metanephric mesenchyme, which form a self-organizing nephron structure in vitro.
Reik and colleagues show that deletion of the large intergenic non-coding RNA H19 leads to unlimited placenta growth. They find that the H19 RNA contains a microRNA that targets the insulin-like growth factor receptor IGF-1R, and demonstrate that the RNA-binding protein HuR prevents miR-675 excision from H19 until miR-675 activity is required to halt placenta growth.
Reprogramming cells towards pluripotency by expression of Oct4, Sox2, Klf4 and c-Myc can be directed towards cardiogenesis by changing the cell culture medium, leading to the formation of spontaneously contracting patches of differentiated cardiomyocytes within ten days.
Oscillating activities of actomyosin networks at the apical side of epithelial cells have been linked to morphogenesis in Drosophila. Montell and colleagues show that myosin oscillations on a polarised actin network at basal cell surfaces of follicle epithelial cells are also required for Drosophila egg chamber elongation.
Cancer-associated fibroblasts (CAFs) promote metastasis by creating tracks for cancer cell migration. Labernadie et al. now show that heterotypic adhesions between E-cadherin on cancer cells and N-cadherin on CAFs transmit forces to drive invasion.
Aguirre-Ghiso and colleagues report that hypoxia in the primary tumour microenvironment leads to upregulation of a dormancy signature in the tumour cells that persists after their dissemination to distant sites, permitting them to evade therapy.
Gottlieb and colleagues demonstrate that glioblastoma cell proliferation under glutamine starvation conditions depends on the glutamine-synthetase-dependent conversion of glutamate to glutamine to fuel purine biosynthesis and cell growth.
Rodeheffer and colleagues show that a high-fat diet in mice activates Akt2 signalling in adipocyte precursors within white adipose tissue deposits, leading to their proliferation and differentiation into adipocytes, and to obesity.
Brown adipose cells contribute to body temperature maintenance by converting lipids and glucose into heat, and can be found in white adipose tissue. Wolfrum and colleagues find a population of cells in white adipose tissue that can adopt brown or white characteristics in response to cold.
Sahai and colleagues report that YAP is required for the establishment and function of cancer-associated fibroblasts. They propose that matrix stiffening promotes Src-mediated activation of YAP in fibroblasts, which is necessary for the cancer-associated fibroblast phenotype and further promotes matrix stiffening in a positive feedback loop.
Werb and colleagues demonstrate that GATA3, a transcription factor that promotes luminal differentiation in the mammary gland, suppresses breast cancer metastasis to the lung by upregulating miR-29b. This microRNA suppresses pro-metastatic characteristics, including mesenchymal traits and the expression of microenvironmental factors involved in angiogenesis and extracellular matrix remodelling.
Bissell, Ghajar and colleagues use organotypic culture systems and in vivo mouse and zebrafish models to reveal the distinct effects of different microvascular niches on tumour cell dormancy. They report that although the stable microvasculature promotes cancer cell quiescence through the production of thrombospondin-1, cancer cells residing near neovascular tips are induced to grow through the action of TGF-β and periostin.
Dimmeler and colleagues show that the atheroprotective transcription factor KLF2 activates expression of the microRNAs miR-143/145 in endothelial cells. miR-143/145 are subsequently enriched in secreted microvesicles and taken up by smooth muscle cells to elicit anti-atherogenic responses.
Del Sal and colleagues demonstrate that the YAP and TAZ effectors of the Hippo pathway are under the control of the mevalonate pathway. They show that mutant p53 and SREBP-dependent activation of mevalonate signalling activates YAP and TAZ and promotes tumour formation in mice, a growth phenotype also conserved in Drosophila.
Following skeletal muscle damage, a population of resident fibro/adipogenic progenitors (FAP) initiates proliferation, resulting in the generation of ectopic white fat but not myofibres. FAPs enhance the differentiation of the myogenic progenitors involved in muscle regeneration.
Cells at the origin of tumour initiation are unknown for many cancers. In hedgehog-induced basal cell carcinoma, skin hair-follicle stem cells do not participate to tumorigenesis, whereas Hedgehog activation in stem cells from the interfollicular epidermis does induce malignancy.
miRNAs can both promote and repress tumorigenesis, and directly control epithelial–mesenchymal transition (EMT). miR-9 (which is upregulated in breast cancer cells) is activated by MYC and MYCN, and regulates EMT and metastasis through direct control of E-cadherin. In contrast, tumour angiogenesis is controlled indirectly through effects on vascular endothelial growth factor (VEGF) expression.
Cancer stem cell activity may not merely be an intrinsic characteristic of a subset of cancer cells and could be regulated by environmental cues. High Wnt activity in human colorectal cancer designates a tumour-initiating population and is orchestrated by the microenvironment.
Administration of spermidine, a polyamine whose concentration declines during ageing, extends lifespan in yeast, flies, worms and in human immune cells. Spermidine prevents early oxidative stress and necrotic cell death and increases the expression of autophagy genes by inhibiting histone acetyltransferases action on histone H3.
Intracellular tau inclusions, a hallmark of several neurodegenerative diseases, propagate in the brain in an unknown fashion. Brain extracts prepared from mice expressing mutated human tau injected into mice expressing wild-type human tau induce the formation and spread of wild-type human tau inclusions.
The epithelial-to-mesenchymal transition transcription factor ZEB1 is involved in metastasis. It is now shown to regulate the tumour-initiating capacity of pancreatic and colorectal cancer cells, through the repression of the stemness-inhibiting miR200s, which are found to inhibit the polycomb repressor Bmi-1.
Human glioblastoma cells release microvesicles containing a diverse set of proteins, miRNAs and mRNAs, which can be taken up by normal host cells that translate the mRNA. Glioma-derived microvesicles carrying the specific tumour markers EGFRvIII and miRNA-21 promote cell proliferation and may serve as a diagnostic tool.