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The molecular mechanisms underlying tumour initiation remain elusive. Here, the authors use spatiotemporally controlled oncogene activation and tumour suppressor inhibition with multi-omics to unveil the role of YAP-mediated oral epithelial progenitor cell reprogramming into tumour-initiating cells.

Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.

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.

The transcriptional regulator YAP is regarded as the universal mechanotransducer, largely from 2D culture studies. Here the authors show that in breast cancer patient tissues and cells in 3D culture, mechanical signals are transduced independently of YAP, questioning YAP as a therapeutic target.

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.

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.

It is unclear how specific signalling pathways are coordinated to generate pathologically activated cancer associated fibroblasts (CAFs). Here, Ferrari et al show that stromal expression of Dickkopf-3 (DKK3) associates with aggressive tumours. DKK3 is a HSF-1 effector that activates β-catenin and YAP/TAZ, and DKK3-driven YAP/TAZ activation regulates the pro-tumorigenic behaviour of CAFs.

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.

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.

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 effectors YAP and TAZ regulate normal and tumorigenic organ growth. Recent studies in vitro and in mouse models have shown that these two transcription co-activators can also promote tissue regeneration. This property could be exploited for regenerative medicine, as long as the therapeutic approaches can minimize the potential for cancer development.

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.

Contractile forces are key to sorting the embryonic inner cell mass from the extraembryonic trophectoderm. Here they show that Lamin-A links changes in mechanical forces to cell fate specification, enabling Yap-Cdx2 signaling in outer, but not inner cells.

Han et al. report that the Hippo pathway kinases LATS1 and LATS2 phosphorylate the heavy metal response transcription factor MTF1, leading to attenuation of heavy metal response gene transcription and cellular detoxification.

Laminin, an important component of the extracellular matrix supporting the epithelium, hinders the typical mechanoresponse of epithelial cells to an increase in substrate stiffness, by protecting the cell nucleus from mechanical deformation.

Inhibition of a cardiac stroma-enriched mechanosensor, SRC—in concert with suppression of the TGFβ pathway—potentiates the reversal of fibroblast activation and alleviates contractile dysfunction in fibrotic hearts.

Non alcoholic fatty liver disease (NAFLD) associates with an elevated risk of developing hepatocellular carcinoma (HCC). Here, the authors find that Nogo-B, an endoplasmic reticulum resident protein, is upregulated by lipid uptake and acts as an oncogene in NAFLD-associated HCC by promoting lipid droplet breakdown by lipophagy and triggering Hippo pathway dysregulation

Mechanotransduction can be defined as translating physical forces into gene expression, which subsequently drives cell fate. Here, Teuscher et al. showed that mechanotransduction across multiple tissues and extracellular matrices is essential for promoting longevity in vivo.

Cellular mechanical forces are regulated by Rho GTPases. Here the authors develop an optogenetic system to control the spatiotemporal activity of RhoA, and show that directing a RhoA activator to the plasma membrane causes contraction and YAP nuclear localization, whereas directing it to the mitochondria causes relaxation.

The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme.

Cancer-associated fibroblasts (CAFs) can produce ECM and form a physical barrier around the tumour. Here, the authors show in transgenic mouse models and in vitro systems that CAFs are able to actively compress cancer cells using actomyosin contractility and this leads to a modulation of cancer cell mechanosensing and tumour reorganisation.

Integrins and talin are parts of a ‘molecular clutch’ that mechanically links the actin cytoskeleton to the extracellular matrix. Elosegui-Artola et al. now reveal a tunable rigidity threshold, above which talin unfolds to mediate force transduction.

How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.

Cells sense mechanical forces from their environment, but the precise mechanical variable sensed by cells is unclear. Here, the authors show that cells can sense the rate of force application, known as the loading rate, with effects on YAP nuclear localization and cytoskeletal stiffness remodelling.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.