Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/ TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ.

YAP and TAZ proteins are transcriptional coactivators encoded by paralogous genes, which shuttle between the cytoplasm and the nucleus in response to multiple inputs, including the Hippo pathway. In the nucleus, they pair with DNA-binding factors of the TEAD family to regulate gene expression. Nuclear YAP/TAZ promote cell proliferation, organ overgrowth, survival to stress and dedifferentiation of post-mitotic cells into their respective tissue progenitors. YAP/TAZ are required for growth of embryonic tissues, wound healing and organ regeneration, where they are activated by cell-intrinsic and extrinsic cues. Surprisingly, this activity is dispensable in many adult self-renewing tissues, where YAP/TAZ are constantly kept in check. YAP/TAZ lay at the center of a complex regulatory network including cell-autonomous factors but also cell- and tissue-level structural features such as the mechanical properties of the cell microenvironment, the establishment of cell–cell junctions and of basolateral tissue polarity. Enhanced levels and activity of YAP/TAZ are observed in many cancers, where they sustain tumor growth, drug resistance and malignancy. In this Cell Science at a Glance article and the accompanying poster, we review the biological functions of YAP/TAZ and their regulatory mechanisms, and highlight their position at the center of a complex signaling network.

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ach tissue has a specific composition of its extracellular matrix (ECM), which is associated with distinctive physical and mechanical properties. These mechanical properties are important for tissue structure, but also control cell function in physiology and disease 1,2. Cells sense the mechanical properties of the ECM through integrin receptors, and measure them by adjusting the contractility of their F-actin cytoskeleton: contractility is maximal when cells are free to spread on stiff ECM substrata, while it is progressively decreased on a soft ECM or in conditions of limited spreading 1. This is sufficient to control the switch between proliferation, differentiation and death in very diverse cell types, by regulating intracellular signalling pathways such as YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif, also known as WWTR1) 3,4 and SRF (serum response factor) 5,6. In support of this model, inhibition of key players that maintain F-actin contractility including the small GTPase RHO, ROCK (RHO kinase), MLCK (myosin light chain kinase) and non-muscle myosin (NMII) induce similar responses to a soft ECM 1. Yet, which other general aspects of cell biology are regulated by mechanical cues, and through which mechanism(s), remain largely unexplored. This is especially true in the case of metabolism, a fundamental engine that is constantly remodelled to match the energetic and biosynthetic requirements of the cell, whose connections to mechanical cues are only starting to emerge 7,8. Results Actomyosin regulates lipid metabolism. To test in an unbiased manner the possibility that actomyosin contractility regulates metabolism we used global metabolomics to compare cells in conditions of high contractility (plated on plastics) with cells in conditions of low contractility, by inhibiting ROCK and MLCK. Analysis of steady-state levels of multiple metabolites indicated clear differences between controls and treated cells (Fig. 1a and Supplementary

The process of metastasis is highly complex 1. In the case of breast cancer, there are frequently long timespans between cells leaving the primary tumour and growth of overt metastases 2, 3. Possible reasons for disease indolence and subsequent transitioning back to aggressive growth include interplay with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance 4-6. However, the signals causing actively growing cells to enter into an indolent state, and enabling them to survive for extended periods of time, are not well understood. In this work, we reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular AT1 cells. This crosstalk promotes the formation of fibronectin (FN) fibrils by indolent cells that drive integrindependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified Secreted frizzled-related protein 2 (Sfrp2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals emanating from lung