Reviews & Analysis

Three-dimensional brain organoid models have come into the spotlight as in vitro tools to recapitulate complex features of the brain. Four recent papers now leverage current technologies to generate new flavours of brain organoids and address aspects of brain biology which, to date, have been challenging to explore.

Cellular senescence, a cell-autonomous growth arrest program, also executes pleiotropic non-cell-autonomous activities through the senescence-associated secretory phenotype (SASP). The innate cGAS–STING DNA-sensing pathway is now shown to regulate senescence by recognizing cytosolic DNA and inducing SASP factors, uncovering an unexpected link between these two previously unrelated pathways.

Obesity now rivals smoking as one of the leading preventable causes of cancer. Obesity-associated neutrophilia is now shown to enhance breast cancer metastasis and to be reversible through dietary modification and weight loss.

The lung undergoes a striking repair process in response to severe injuries such as influenza infection. A study now demonstrates that associated stem/progenitor cells are heterogeneous in nature and comprise subpopulations dominated by hypoxia/Notch or Wnt signalling. Modulation of this heterogeneity in favour of functional repair may have therapeutic value.

CCCTC-binding factor (CTCF) sites are enriched at the boundaries of topologically associated domains (TADs), but their function within TADs is unclear. Removal of sub-TAD CTCF sites adjacent to the α-globin enhancers is now shown to result in inappropriate activation of neighbouring genes. Intra-TAD enhancer insulation might be broadly important for tissue specificity of enhancers.

Mutations in AT rich interactive domain 1A (ARID1A) are common in ovarian cancers. A study now shows that HDAC6 activity is required for survival of ovarian cancer cells bearing ARID1A mutations. HDAC6 inhibition selectively promotes apoptosis of ARID1A-inactivated cells, supporting the use of HDAC6 inhibition in the treatment of clear cell ovarian cancer.

In this Review, Prinz and co-authors discuss the role of the endoplasmic reticulum (ER) in the de novo generation of peroxisomes, lipid droplets and omegasomes, and how this requires subdomains with specific protein and lipid compositions.

The mechanism of action of oncogenes in acute myeloid leukaemia is poorly understood. A study now shows that the fusion oncoprotein AML1-ETO regulates leukaemogenesis by increasing the expression of small nucleolar RNAs through post-transcriptional mechanisms, resulting in increased ribosomal RNA methylation, protein translation, and promotion of leukaemic-cell self-renewal and growth.

Haem is an iron-containing cofactor required for life. Many cellular processes rely on haem and failure to maintain iron homeostasis results in numerous pathological conditions. A study now identifies a Caenorhabditis elegans inter-organ signalling pathway in which secreted intestinal HRG-7 and neuronally secreted BMP signals coordinate animal haem homeostasis.

Several markers of gastric stem cells have been identified in recent years. Now a study demonstrates that Lgr5 marks a population of reserve stem cells located at the base of the corpus glands of the gastric epithelium, and that these cells can also act as a cell-of-origin for gastric tumorigenesis.

The endosomal sorting complex required for transport (ESCRT)-III is critical for membrane abscission; however, the mechanism underlying ESCRT-III-mediated membrane constriction remains elusive. A study of the dynamic assembly and disassembly of the ESCRT-III machinery in vitro and in vivo now suggests that the turnover of the observed spiralling filaments is critical for membrane abscission during cytokinesis.

Fusion between the inner membranes of two mitochondria requires the GTPase optic atrophy 1 (OPA1), but the molecular mechanism is poorly understood. A study now shows that fusion of two liposomes can be performed by OPA1 tethered to just one liposome, through an interaction with the phospholipid cardiolipin on the opposing liposome.

Physical forces influence the growth and development of all organisms. In the second Review in the Series on Mechanobiology, Trepat and co-authors describe techniques to measure forces generated by cells, and discuss their use and limitations.

Due to their varied metabolic and signalling roles, mitochondria are important in mediating cell behaviour. By altering mitochondrial function, two studies now identify metabolite-induced epigenetic changes that have profound effects on haematopoietic stem cell fate and function.

Epithelial cells form energetically costly cell–cell adhesions in response to mechanical forces. How cells obtain their energy during this event is unclear. Activity of a key regulator of cell metabolism, the AMP-activated protein kinase (AMPK), is now shown to be mechanoresponsive, and thus can bridge adhesion mechanotransduction and energy homeostasis.

Little is known regarding how the interactions of stem cells with the immune system regulate their plasticity. A study now describes a mechanism by which normal breast and cancer stem cells utilize miR-199a to downregulate the corepressor LCOR and minimize responses to type I interferon.

Vascular malformations result from improper blood vessel responses to molecular and mechanical signals. Two studies now show that endothelial cell migration and cell shape changes are perturbed in mutants lacking the TGFβ/BMP co-receptor endoglin, leading to arteriovenous shunts. Endoglin coordinates endothelial cell responses to ligand–receptor signalling and flow-mediated mechanical cues.

The involvement of proliferation and migration in epidermal healing has long been recognized, but three studies now reveal how a variety of individual cell behaviours achieve a collective epithelial response, and how diverse repair routes are taken by cells of different origins.

In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development.

Dysfunctional cells are eliminated from epithelial monolayers by a process known as cell extrusion to maintain tissue homeostasis. Normal epithelial cells are now shown to induce the extrusion of oncogene-transformed cells by inducing metabolic changes in the oncogene-expressing cells through PDK4-mediated inhibition of PDH and mitochondrial metabolism.