Reviews & Analysis

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.

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.

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.

Stefano Piccolo and co-authors review recent insights into how YAP and TAZ transcription factors respond to the tissue environment, and how they mediate altered cell behaviour. Feedback mechanisms and crosstalk with other pathways are discussed, as are outstanding questions in the field.

Celia-Terrassa and Kang discuss specialized functions of distinct metastatic niches, and how the emerging knowledge can be leveraged for improved therapeutic opportunities.

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.

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.

Shahbazi et al. review our current understanding of the post-implantation mammalian embryo and how innovative technologies have helped to shape it.

Mitochondria sense and respond to many stressors and can support cell survival or death through energy production and signalling pathways. Mitochondrial responses depend on fusion–fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, such as with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.

Tumours are often more stiff than normal tissue. In this Review, Mohammadi and Sahai discuss recent insights into how such altered tumour mechanics arise and how this affects tumorigenesis.

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.

Specific combinations of mutations cause unique signalling and metabolic requirements. Concurrent G-protein α_s (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.

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.

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.

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.

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.

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.

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.

A history of autophagy. In this Perspective, Mizushima describes the leaps and bounds in the history of autophagy and discusses unanswered questions driving the field forward.