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Vanni et al. show a role for microtubules in YAP/TAZ mechanosignalling. Mechanoresponsive microtubule reorganization into centrosomal arrays allows for AMOT delivery to pericentrosomal proteasomes and degradation, leading to YAP/TAZ activation.

Marco Sandri, Helge Amthor, Stefano Piccolo and colleagues show that BMP signaling is a key positive regulator of muscle hypertrophy. They further show that inhibiting BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin knockout mice and exacerbates the effects of denervation and fasting.

SHARP1, which is itself regulated by the p63 metastasis suppressor, regulates the invasive and metastatic phenotype in triple-negative breast cancer (TNBC) through inhibition of hypoxia-inducible factors, and this process operates independently from oxygen levels.

Piccolo and colleagues perform integrated single-cell analyses and identify YAP/TAZ regulation of glioma stem cell differentiation as a core dependency for tumor maintenance.

In the TGFβ pathway, receptor-activated SMADs (R-SMADs) associate with SMAD4 to regulate transcription. Piccolo and colleagues reveal that the deubiquitylase USP15 is required for TGFβ responses by reversing R-SMAD ubiquitylation and thereby promoting the retention of the SMAD complex at promoters.

Interdependence between YAP/TAZ and BRD4 drives transcriptional addiction in cancer cells and determines sensitivity to BET inhibition.

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.

Receptor tyrosine kinase (RTK)–Ras oncogenes have now been shown to reprogram normal primary human and mouse cells into tumour precursors by empowering cellular mechanotransduction, in a process requiring permissive extracellular-matrix rigidity and intracellular YAP/TAZ/Rac mechanical signalling sustained by activated oncogenes.

Notch signalling is a fundamental negative regulator of epidermal stemness. Here, the authors show that cell mechanics through YAP/TAZ activity prevent primary human keratinocytes from differentiating by inhibiting cell-autonomous Notch signals.

Microfluidic reprogramming of human somatic cells to induced pluripotent stem cells is rapid and highly efficient, enabling large-scale derivation from patient cells as well as seamless on-chip differentiation without cell expansion.

Mechanical stresses that are intrinsic to the early shape-forming movements of embryonic tissues have now been shown to play essential and evolutionarily conserved parts in cell-fate specification.

Three classic papers helped reveal how the Spemann organizer builds the vertebrate body.

Forces transmitted through cell–cell and cell–extracellular matrix adhesions control cell fate decisions. But how are mechanical cues translated into gene expression programmes? The transcriptional regulators YAP and TAZ have arisen as convergence points of mechanical and biochemical signals.

The ARID1A-containing SWI/SNF complex operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ; this interaction is regulated by cellular mechanotransduction.

Reactivation of 'metastasis suppressor' genes holds great promise for the treatment of incurable malignancies. To date, only a few of these genes have been identified. A new study shows that breast cancer metastasis can be blunted by leukemia inhibitory factor (LIF) signaling through regulation of the Hippo pathway, linking metastatic growth to the regulation of a pathway involved in building organs during development (pages 1511–1517).

tDeclining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity, so sustaining YAP/TAZ mechanosignalling or inhibiting STING present promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

Generation of the organizer tissue is induced on the dorsal side of the developing embryo by an asymmetry in Nodal signalling, which is only sufficiently high dorsally to induce organizer-specific gene expression. Now, through the identification of a microRNA (miR-15 and miR-16) that targets the Nodal receptor, microRNA is shown to have a role in this process.

The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.

Signalling pathways are ideal candidates for microRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Emerging evidence suggests that microRNAs affect the responsiveness of cells to various growth factors, serving as nodes of signalling networks that ensure homeostasis and regulate disease.

Piccolo and colleagues report that the YAP/TAZ factors form ternary complexes with TEAD and AP-1 factors to drive a transcriptional program that promotes cell proliferation and tumour growth.

The nucleus is a mechanically stiff organelle of the cell and the DNA damage response protein ATR can localize to the nuclear envelope upon mechanical stress. Here, the authors show that ATR may contribute to the integrity of the nuclear envelope and may play a role in cell migration.

A modified brain-organoid culture generates extensive axon outgrowth with specific tract-like patterns. Organoid tracts connect neurons across distant sites and can innervate and stimulate co-cultured mouse spinal cord tissue to elicit muscle contractions.

Piccolo and colleagues discuss the current knowledge on YAP/TAZ biology in cancer, highlighting recent progress in the field and discussing open questions, as well as potential clinical implications.

Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.

Nowell et al. report that chronic inflammation of the corneal epithelium activates β-catenin signalling through YAP/TAZ-dependent mechanotransduction, leading to epidermal differentiation on the ocular surface and corneal squamous cell metaplasia.

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.

Epidermal cultures can treat skin diseases, such as Junctional Epidermolysis Bullosa, but the signature of stem cells is unclear. By single cell RNAseq analyses on human keratinocytes, the authors identify the molecular profile of holoclones and the role of FOXM1 in regulating the proliferative potential of epidermal stem cells.

The transcription factors YAP and TAZ have recently emerged as being conserved transducers of mechanical signals into cells and mediators of processes such as proliferation, migration and cell fate decision. The roles of YAP-mediated and TAZ-mediated mechanotransduction have now been documented in many physiological and pathological contexts, providing novel insights into cellular mechano-responses and their consequences.

Ong et al. report how YAP/TAZ and mTORC1 signalling intersect in endothelial cells to regulate nutrient acquisition and vascular growth.

The transcriptional activators YAP and TAZ have been discussed mainly for their cell-autonomous functions in cancer. Recent studies suggest their emerging roles in orchestrating tumour–stroma interactions, acting as a signalling hub, as discussed in this Review article.

The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.

Biomaterials have been utilized widely to study cellular mechanotransduction. This Review discusses how cells respond to mechanical cues elicited by a range of biomaterial characteristics via YAP/TAZ mechanosensitive transcriptional factor activity.

Ingallina et al. show that mutant p53 is protected from degradation in response to matrix stiffness in a manner dependent on RhoA geranylgeranylation and actomyosin dynamics.

Cyclin-dependent kinase 2 (cdk2) is surprisingly found to suppress senescence induced by the Myc oncogene in various cell types. Inactivation or deletion of cdk2 sensitizes mouse embryonic fibroblasts to Myc-induced senescence via a mechanism requiring pRb and p53.