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The Hippo pathway transcription factors YAP and TAZ are often thought to play redundant roles in cancer progression. Here, Patterson et al demonstrate that TAZ is specifically required in HPV18+ cervical cancer, a subtype associated with worse prognosis.

Anerillas et al. provide a strategy to eliminate senescent cells that leverages on their secretory needs. Inhibiting YAP–TEAD triggers endoplasmic reticulum stress that eliminates senescent cells from several tissues, improving age-related fibrosis.

The mechanisms driving metabolic dysfunction in obesity remain incompletely understood. Here, the authors show that the levels of Hippo pathway effector YAP are reduced in muscle from individuals with insulin resistance and obese-diabetic mice, and that YAP promotes skeletal muscle lipid metabolism and limits adiposity in obese mice.

Intracellular detection of viral invasion triggers activation of the transcription factor IRF3 and antiviral interferon production. Fangfang Zhou and colleagues report that the transcription regulator YAP in the host restrains this process by preventing inadvertent spontaneous dimerization of IRF3 and its translocation to the nucleus.

Matrix viscoelasticity regulates cell behavior in a stiffness-dependent manner. Here, the authors reveal that the mechanosensitive channel Piezo1 transduces soft matrix viscoelastic cues, through a coordinated interaction with molecular clutch mechanisms.

Failure of the ependymal cell layer that lines the ventricular surfaces of the brain can result in fetal hydrocephalus. Park et al. reveal a role for the Hippo pathway gene Yap in the generation of ependymal cells, and show that suppression of Yap is observed in a model of hydrocephalus.

Cox et al. report that Yap induces the expression of glutamine synthetase, thereby elevating glutamine and nitrogen levels for de novo nucleotide synthesis. They show that this promotes hepatomegaly and growth of liver cancer cells in zebrafish.

Matrix stiffness induced nuclear deformation regulates gene expression. This study finds that cell spreading on a stiff matrix induces tension in the nuclear lamina which promotes nuclear localization of yes associated protein (YAP), a transcriptional co-activator.

Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.

Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.

Intercalated discs ensure mechanical and electrochemical coupling during contraction of the heart. Here, the authors show that loss of Xinβ results in cardiomyocyte proliferation defects and cardiomyopathy by influencing the Hippo-YAP signalling pathway, thus affecting cardiac development and function.

Cells respond to mechanical signals during development and after injury. Poitelon et al. report for the first time that myelin-forming glia activate the Hippo pathway effectors Yap and Taz in response to mechanical stimuli, and that they are required for Schwann cell development and myelination in vivo.

Li et al. show that ROR1–HER3 receptor tyrosine kinase signalling in breast cancer cells inhibits the MST1/2 Hippo pathway kinases through a lncRNA termed MAYA. The resulting activation of YAP promotes osteoclast differentiation for bone metastasis.

Li et al. define an adaptive resistance mechanism against FGFR inhibitor treatment in breast cancer attributed to loss of BRG1 chromatin recruitment, reactivation of YAP-dependent enhancers and upregulation of amino acid-induced mTORC1 activity.

The Hippo pathway is frequently dysregulated in cancer. Here, the authors identify NUAK2 as negative regulator of the Hippo pathway from a siRNA kinome screen and show that NUAK2 promotes YAP/TAZ nuclear localisation while NUAK2 is a transcriptional target of YAP/TAZ, thus providing a feed forward loop to promote tumorigenesis.

Camargo and colleagues employed an RNAi screen to identify LKB1 as an upstream regulator of the Hippo pathway. They show that LKB1 regulates SCRIB localization through the MARK kinase, leading to regulation of the activity of YAP through MST1/2 kinases.

Antifibrotic therapies that target myofibroblast activation are needed to treat chronic liver disease. Here the authors identify an axis of integrin beta-1 expression and Yap-1 and Pak protein signalling that can be interfered with to inhibit myofibroblast function and liver fibrosis in vivo.

Deletion of upstream tumor suppressors of the Hippo/YAP pathway is frequent in papillary renal cell carcinoma (pRCC). Here, the authors employ a transgenic mouse model, single-cell transcriptomics and public genomic datasets to show that targeting hyperactivated YAP1 prevents neoplastic renal epithelial cell immune evasion and impairs the development of pRCC.

By deciphering the transcriptional network of human embryonic pancreatic progenitors, Ferrer and colleagues identify the Hippo-responsive transcription factor TEAD1 as a regulator of the pancreatic progenitor enhancer programme.

Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.

This study finds that the Hippo pathway is essential for gut epithelial regeneration and tumour initiation; the Hippo component Yap holds off differentiation of intestinal stem cells to Paneth cells to promote a survival and self-renewal regenerative program through activation of the Egfr pathway.

In two related papers, Chen and colleagues and Guan and colleagues report a crucial role for the AMPK and Hippo pathways in glucose homeostasis. Starvation triggers AMPK-mediated phosphorylation and inactivation of YAP.

The underlying mechanism of acquired resistance to targeted therapy in cancer remains to be explored. Here, the authors show that upregulation of the FOSL1 transcription factor restores YAP/TEAD occupancy on chromatin to drive resistance to GNE-7883, an allosteric TEAD inhibitor.

Branching morphogenesis is essential for the formation of most epithelial organs. Here, the authors show that Neurofibromatosis 2 (NF2), the Hippo pathway kinases LATS1 and LATS2, and the transcriptional co-activators YAP and TAZ control tip identity, RET signalling and branching morphogenesis in the mouse kidney.

YAP has previously been identified as an oncogene that promotes cell growth, but now it is shown to restrict stem cell expansion during regeneration in the mouse intestine, suggesting that it may function as a tumour suppressor in colon cancer.

Liu et al. show that statin enhances cardiovascular disease protection through epigenetic modulation of YAP–SOX9 signaling, improving endothelial function and offering new therapeutic strategies.

The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.

Using visible-light-induced crosslinking, a local stiffening approach is developed for ex vivo mouse and human lung tissue as an early lung injury model, directing epithelial cell mechanosensing, differentiation and nascent protein deposition.

Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.

The authors investigated the contribution of yes associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in osteocyte mechanotransduction. In a 3-D osteocyte compression model, they show that YAP/TAZ signaling is activated, is required for osteocyte mechano-responsiveness, and regulates the expression profile of target genes as shown by RNAseq analysis and the control of chemokine expression.

The Hippo pathway is a major orchestrator of organ development and homeostasis. Here Azad and colleagues develop a biosensor to monitor the activity of the Hippo pathway component LATS and identify VEGF signalling as an upstream regulator of LATS, supporting a role for Hippo signalling during angiogenesis.

LATS1/2 kinases are reported to be tumour suppressors in many cancers. Here the authors show that conditional deletion of LATS1/2 in the mature mouse luminal mammary epithelium leads to luminal-basal plasticity and development of basal-like carcinomas.

It is unclear how epithelial tissues adjust cell division rates to cell density. Here, the authors show that Plexin-B1 and Plexin-B2 sense mechanical compression (crowding) of epidermal stem cells, resulting in inactivation of YAP and suppression of cell proliferation.

Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

N-cadherin can alter how the stiffening extracellular microenvironment is interpreted by mesenchymal stem cells, leading to subsequent changes in downstream cell proliferation and differentiation.