News & Views

  • News & Views |

    Different subclones cooperate to support tumour heterogeneity and growth, but the effect on metastasis is unclear. A new study now shows that, as non-cell-autonomous drivers, minor cancer cell subclones instigate growth at distant sites of otherwise non-metastatic cancer cells. This is mediated systemically by perturbation in the metastatic tissue.

    • Luigi Ombrato
    •  & Ilaria Malanchi
  • News & Views |

    The ability of cancer cells to adapt to external and internal stresses is critical for tumourigenesis. A new study now shows that the integrated stress response is critical for tumour cell adaptation to stress induced by c-MYC activation, providing mechanistic insights into tumour responses to intrinsic stresses with implications for cancer therapies.

    • Kirk A. Staschke
    •  & Ronald C. Wek
  • News & Views |

    Tumour-secreted microvesicles carry bioactive molecules that can be transferred to recipient cells, impacting tumour progression. A study now shows that ARF6 drives miRNA loading into tumour microvesicles through interaction with pre-miRNA–Exportin-5 complexes, thus shedding light on specific cargo packaging mechanisms.

    • Gonçalo Rodrigues
    • , Haiying Zhang
    •  & David Lyden
  • News & Views |

    Centromere identity must be maintained through multiple generations. A new study reveals a Constitutive Centromere-Associated Network (CCAN)-dependent retention of CENP-A, a key epigenetic mark for centromeres, in centromeres during DNA replication and a replication-dependent error correction to eliminate ectopic CENP-A in chromosome arms.

    • Masatoshi Hara
    •  & Tatsuo Fukagawa
  • News & Views |

    Embryonic stem cells derived from the inner cell mass can differentiate to all embryonic lineages of any adult cell type and to a limited extent to extra-embryonic tissues. A study now allows the generation of pig and human stem cells with enhanced differentiation potential towards all embryonic and extra-embryonic fates, one step closer to the totipotent state of the fertilized egg.

    • Fred Etoc
    •  & Ali Brivanlou
  • News & Views |

    IRE1α is an endoplasmic reticulum (ER) transmembrane protein known for a crucial role in regulating the unfolding protein response. A study now shows that IRE1α interacts with the main ER Ca2+ channel InsP3Rs and facilitates the transfer of Ca2+ from the ER into mitochondria, thus driving cellular metabolism.

    • Roland Malli
    •  & Wolfgang F. Graier
  • News & Views |

    Yap signalling is crucial for intestinal regeneration, but its role is largely dispensable in homeostasis. Two studies now reveal Yap-dependent mechanisms of intestinal regeneration and tissue organization: transient expansion of a rare cell type after damage in vivo and Notch–Dll activation for symmetry breaking in organoid development.

    • Vivian S. W. Li
  • News & Views |

    Rag GTPases play a crucial role in mTORC1 activation by promoting its recruitment to the lysosomal surface in a nutrient-dependent manner. A study now identifies a family of lysosomal G-protein-coupled receptors as modulators of Rag GTPases localization and activation, adding one more component to the fast-growing mTOR regulatory network.

    • Rosa Puertollano
  • News & Views |

    Haematopoietic stem cells (HSCs) are maintained in vivo by intrinsic programs and extrinsic niche signals. Ex vivo expansion of HSCs is limited, owing to reduced stem cell maintenance factors. A study now shows that rejuvenated niche cells can be obtained by transcriptional rewiring of specific genes that maintain and expand HSCs ex vivo.

    • Aparna Venkatraman
    •  & Linheng Li
  • News & Views |

    Components of the spliceosome are frequently mutated in haematopoietic malignancies. Identification of mis-spliced genes promoting transformation will uncover novel targeted therapies. Now, a long isoform of IRAK4 is shown to be upregulated in a subset of acute myeloid leukaemia patients, conferring susceptibility for IRAK4 inhibition therapy.

    • Maria Guillamot
    •  & Iannis Aifantis
  • News & Views |

    Osteoclasts are known for their role in bone resorption. A study now shows that a vascular–associated osteoclast subtype at the growth plate also regulates blood vessel growth in bone and is supported by type H endothelial cells. These type H capillaries, in turn, release proteinases that promote cartilage degradation.

    • Jameel Iqbal
    •  & Mone Zaidi
  • News & Views |

    MicroRNAs (miRNAs) repress target mRNAs, often with exquisite tissue specificity. Wang et al. exploit the specific expression of miRNAs to regulate guide production for Cas9. Their method enables novel strategies to simultaneously measure the activity of multiple miRNAs and restrict Cas9 binding or genome editing to precisely defined cell types.

    • Karina Jouravleva
    •  & Phillip D. Zamore
  • News & Views |

    HIV particles incorporate host membrane proteins into their envelope to evade the immune system and infect other cells. A study now shows that Gag assembly on the host cell membrane produces a raft-like nanodomain favourable for protein partitioning due to a transbilayer coupling mechanism assisted by long saturated chain lipids and cholesterol.

    • Joanna Podkalicka
    •  & Patricia Bassereau
  • News & Views |

    Macrophages modulate mammary tumour response to chemotherapy. A new study shows that targeted elimination of macrophages elicits a type I interferon response in the tumour microenvironment that enhances the efficacy of platinum- but not taxane-based chemotherapy, underscoring complex regulatory roles for macrophages in chemotherapy-treated tumours.

    • Michele De Palma
    • , Sina Nassiri
    •  & Chiara Cianciaruso
  • News & Views |

    Epithelial–mesenchymal transition (EMT) is crucial for development, and for dissemination and invasion of cancer cells. A study now identifies the apical–basolateral polarity status of epithelia as a checkpoint for EMT induction and tumour metastasis through aPKC–Par3-regulated degradation of the EMT transcription factor SNAI1.

    • Oana-Diana Persa
    •  & Carien M. Niessen
  • News & Views |

    Healthy and malignant haematopoietic stem cells (HSCs) must overcome a variety of cell intrinsic and extrinsic stresses to maintain their functionality. Now, IRE1α –XBP1 signalling is shown to protect HSCs and to promote survival of, and confer competitive advantages to, NRAS-mutated pre-leukaemic cells.

    • Marina Scheller-Wendorff
    •  & Carsten Müller-Tidow
  • News & Views |

    Cell metabolism ensures that cell dynamics and continued renewal are supported by a constant flow of matter that consumes energy. A new study shows that cell metabolism is sensitive to mechanical cues, revealing that the level of cell contraction modulates the production and storage of lipids, which could serve as fuel for energy production.

    • Manuel Théry
    •  & Mario Pende
  • News & Views |

    Patients with diabetes could benefit from cell-based insulin therapy, but the supply of human islet tissue is limited. A study now reports an approach in which human-pluripotent-stem-cell-derived islet β-cells are purified and re-aggregated to generate cells that more closely resemble mature human β-cells.

    • Hans E. Hohmeier
    • , Jie An
    •  & Christopher B. Newgard
  • News & Views |

    AKT, also known as protein kinase B, is one of the most frequently dysregulated serine/threonine kinases in cancer, and its hyperactivity drives tumorigenesis and chemotherapy resistance. Two studies now find that AKT methylation by the methyltransferase SETDB1 is an early step in its oncogenic activation.

    • Amelia K. Luciano
    •  & David A. Guertin
  • News & Views |

    Stressed eukaryotic cells store mRNAs in protein-rich condensates called stress granules. Using single-molecule tracking techniques to examine how mRNAs enter stress granules, a new study shows that mRNAs make transient contacts with the granule surface before stable association, and become largely immobile after entry.

    • Chih-Yung Lee
    •  & Geraldine Seydoux
  • News & Views |

    It is commonly accepted that disseminated tumour cells survive cytotoxic chemotherapy because they are not proliferating. A new study now finds that, in contrast to this long-standing concept, both dormant and proliferative cancer cells can be protected from chemotherapy when they reside at the perivascular niche.

    • Melanie Werner-Klein
    •  & Christoph A. Klein
  • News & Views |

    Ancestral experience of mitochondrial stress is now found to render progeny of the roundworm Caenorhabditis elegans more resistant to the same insult for up to four generations. A DNA modification, N6-methyldeoxyadenine, is implicated in the inheritance of this stress adaptation.

    • Sarah-Lena Offenburger
    • , Marcos Francisco Perez
    •  & Ben Lehner
  • News & Views |

    RIPK1 plays a key role in several inflammatory and cell death signalling pathways. Understanding its regulation is pivotal for identifying diseases that might therapeutically benefit from RIPK1 inhibition. Recent studies now show that TBK1 and IKKε constitute a cell death checkpoint that restrains RIPK1 activation.

    • Klaus Heger
    •  & Vishva M. Dixit
  • News & Views |

    BAF is a heterogenous chromatin-remodelling complex, frequently mutated in cancer. A study now defines genome-wide localization patterns of three complexes, cBAF, PBAF and previously unknown ncBAF, and reveals the ncBAF complex as a specific vulnerability in synovial sarcoma and malignant rhabdoid tumours.

    • Divya Reddy
    •  & Jerry L. Workman
  • News & Views |

    During mitosis, the kinetochore connects chromosomes to spindle microtubules and enables chromosome segregation. A genetic study in vertebrate cells demonstrates phosphorylation-regulated plasticity of kinetochore assembly and highlights the role of the centromere protein T in load-bearing kinetochore–microtubule attachment.

    • Yang Yang
    •  & Hongtao Yu
  • News & Views |

    Newly synthesised lysosomal proteins are sorted from other cargo on the secretory pathway for delivery to endolysosomal compartments. A study now shows that the Batten disease protein, CLN8, acts as a recycling receptor to sort soluble lysosomal enzymes for export from the endoplasmic reticulum to the Golgi.

    • J. Paul Luzio
  • News & Views |

    The cancer-suppressive mechanisms underlying a tissue’s response to spontaneous oncogenic mutations during homeostasis are largely unknown. A study now explores how clonal expansion of epidermal stem cells with specific oncogenic mutations might be restricted by their elimination through enforced differentiation.

    • Paola Kuri
    •  & Panteleimon Rompolas
  • News & Views |

    Classical actin-dependent, integrin-mediated cell–matrix adhesions disassemble before mitotic rounding. Yet, to transmit positional information and facilitate daughter-cell separation, dividing cells maintain connections to the matrix. A previously unidentified class of actin-independent integrin adhesions may fulfil this task.

    • Ronen Zaidel-Bar
  • News & Views |

    β-catenin regulates cell–cell adhesion and maintains stemness through Wnt signalling, but how these functions are mechanistically related is not fully understood. A study now identifies CRAD as the mechanistic link, providing insight into how dysregulation of epithelial adhesion contributes to Wnt-driven tumorigenesis.

    • George Eng
    • , Jonathan Braverman
    •  & Ömer H. Yilmaz
  • News & Views |

    Functional genetic screening of mice and other mammals is exceedingly challenging. A CRISPR-based mutagenesis screen in mice has successfully revealed amino acids vital for protein function of the DND1 gene, missense mutations of which lead to defects in primordial germ cell development.

    • Yevgeniy V. Serebrenik
    •  & Ophir Shalem
  • News & Views |

    The intestinal crypt has become the prototype compartment to investigate adult stem cell biology, and the list of identified intestinal stem cell (ISC) markers is already extensive. A comprehensive study now uncovers an additional layer in ISC regulation by introducing long noncoding RNA lncGata6 to the stem cell repertoire.

    • Pantelis Hatzis
    •  & Hugo J. G. Snippert
  • News & Views |

    Intra-tumour heterogeneity manifests both at the level of mutational burden, and at a functional level within genetically homogenous populations. A new modelling approach suggests stemness within colorectal tumours is defined by microenvironmental cues secreted from cancer-associated fibroblasts rather than cell-intrinsic properties.

    • D. J. Flanagan
    • , M. C. Hodder
    •  & O. J. Sansom
  • News & Views |

    Paraspeckles are nuclear bodies built on the long noncoding RNA, NEAT1, that regulate cellular homeostasis, but how they sense and help under stress is unclear. A study now shows mitochondrial stress modulates paraspeckles by altering NEAT1 expression with a feedback loop that influences mitochondrial homeostasis.

    • Archa H. Fox
  • News & Views |

    Ferroptosis is a regulated non-apoptotic form of cell death and its functional role in tumorigenesis remains elusive. A study now shows that the tumour suppressor BAP1 enhances ferroptosis by modulating expression of the cystine transporter SLC7A11, leading to improved control of tumour growth.

    • Michael P. Murphy
  • News & Views |

    Rag GTPases facilitate mTORC1 activation by recruiting it to Rheb at the lysosome when amino acids are abundant. A study now shows that the amino acid-induced change in the GTP/GDP-binding state of the Rag heterodimer paradoxically increases its dynamic release from the Ragulator at the lysosome and may limit mTORC1 activation.

    • Aaron M. Hosios
    •  & Brendan D. Manning
  • News & Views |

    Maintaining plasma membrane tension is important for eukaryotic cells. How altered membrane tension is sensed and relayed to downstream factors, such as the target of rapamyin complex 2 (TORC2), is poorly understood. Reorganization of a signalling lipid into discrete membrane domains is now shown to inactivate TORC2 in yeast.

    • Michael Ebner
    •  & Volker Haucke
  • News & Views |

    During embryo development, concentration gradients of signalling molecules instruct formation of different cell types. How these gradients adapt to variable embryo sizes to form a properly scaled individual remains elusive. A simple system of an activator and an inhibitor, with different diffusion properties, may give an answer.

    • Laurence Garric
    •  & Jeroen Bakkers
  • News & Views |

    A previously unidentified protein complex termed Shieldin acts with the nucleosome-binding protein 53BP1 to limit end resection at DNA double-strand breaks, impacting myriad biological outcomes, from immunology to cancer therapy, and highlighting the importance of chromatin responses to DNA damage in vertebrates.

    • Roger A Greenberg
  • News & Views |

    Skeletal muscle denervation leads to myofibre atrophy with fibrosis and fatty infiltration of muscle-resident fibroadipogenic progenitors (FAPs). A study shows that on denervation, FAPs activate pathogenic STAT3–IL-6 signalling. Inhibition of this pathway prevents atrophy and points to potential therapeutic targets.

    • Giovanna Marazzi
    •  & David Sassoon
  • News & Views |

    Metastatic colonization of distant organs is the prime cause of mortality from cancer, and is governed by a series of steps that include survival and growth in the perivascular niche. A study now shows that L1CAM is necessary for tight physical interactions in this niche, involving a YAP–MRTF–β1-integrin mechanotransduction pathway.

    • Matthia A. Karreman
    •  & Frank Winkler
  • News & Views |

    Enteroendocrine (EE) cells secrete diverse peptide hormones, regulating food intake, digestion and metabolism. A study now challenges the traditional view that each hormone is the dominant product of a distinct EE cell type, showing that in response to local cues the same cell produces different hormones in different tissue compartments.

    • Ramesh A. Shivdasani
  • News & Views |

    The metabolic phenotype of tumours is shaped by a complex interplay between cancer cells and their microenvironment. Two studies now show that aspartate acquisition is a metabolic limitation encountered by certain tumours in their native in vivo environment, and that overcoming this limitation is advantageous for tumour growth.

    • Accalia Fu
    •  & Nika N. Danial
  • News & Views |

    Specific combinations of mutations cause unique signalling and metabolic requirements. Concurrent G-protein αs (GNAS) and KRAS mutations in a subset of pancreatic tumours are now shown to inhibit SIK kinases through aberrant cAMP–PKA activation, triggering a metabolic program defined by lipid metabolism and fatty acid oxidation.

    • Pablo E. Hollstein
    •  & Reuben J. Shaw
  • News & Views |

    AMPK is a key metabolic sensor promoting cellular energy homeostasis under low-nutrient conditions and other stresses. However, its role in cancer is context-dependent and not fully understood. A study now shows that glioma stem cells co-opt an AMPK-dependent pathway to rewire metabolism, promoting tumour growth.

    • Nektaria Maria Leli
    •  & Constantinos Koumenis
  • News & Views |

    The transition from a fertilized egg to a pluripotent and transcriptionally independent embryo requires multi-layered chromatin regulation. A study now provides simultaneous profiling of chromatin accessibility and DNA methylation in human preimplantation embryos at single-cell resolution.

    • Raquel Pérez-Palacios
    •  & Deborah Bourc’his
  • News & Views |

    Multiple clones of cancer cells co-exist within a tumour, and yet it is not clear when these subclones arise and how they contribute to tumour progression. A multicolour clonal tracing study now shows that benign skin tumours are mostly monoclonal while the more advanced lesions are composed of multiple intermixed subclones.

    • Michalina Janiszewska
    •  & Kornelia Polyak
  • News & Views |

    Phase separation can build assemblies and regulate biological function. Two articles link specific forms of protein and RNA degradation to phase separation. The polyubiquitin shuttle factor UBQLN2 localizes to stress granules where it may extract ubiquitinated proteins, and the miRISC complex functions through phase separation.

    • Tanja Mittag
    •  & Nicolas L. Fawzi
  • News & Views |

    The establishment of the two distinct lineages that form the branched epithelial ductal tree of the mammary gland is a complex and essential developmental process. Two independent studies now describe the switch from multipotency to unipotency as an embryonic process and outline mechanisms of early lineage restriction.

    • Philip Bland
    •  & Beatrice A. Howard
  • News & Views |

    De novo assembly of microtubules, nucleation, has remained surprisingly enigmatic, considering that microtubules are polymers of only two proteins, α- and β-tubulin, and that γ-tubulin has a well-established role as nucleator. Now, the tubulin polymerase XMAP215 is shown to be required for efficient nucleation in cooperation with γ-tubulin.

    • Jens Lüders
  • News & Views |

    Brd4, a reader of histone acetylation, is a transcriptional co-activator implicated in the maintenance of embryonic stem cells (ESCs). A study now shows that Brd4 is dispensable in mouse ESCs maintained in ground state pluripotency, and that cooperative activity of Tet1/2 and ESC-specific transcription factors compensates for its loss.

    • Yaser Atlasi
    •  & Hendrik G. Stunnenberg