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Autophagy, besides ensuring energy metabolism and organelle renewal, is crucial for the biology of adult normal and cancer stem cells. However, it remains incompletely understood how autophagy connects to stemness factors and the nature of the microenvironmental signals that pattern autophagy in different cell types. Here we advance in these directions by reporting that YAP/TAZ transcriptionally control autophagy, being critical for autophagosomal degradation into autolysosomes. YAP/TAZ are downstream effectors of cellular mechanotransduction and indeed we found that cell mechanics, dictated by the physical property of the ECM and cytoskeletal tension, profoundly impact on autophagic flux in a YAP/TAZ-mediated manner. Functionally, by using pancreatic and mammary organoid cultures,we found that YAP/TAZ-regulated autophagy is essential in normal cells for YAP/TAZ-mediated dedifferentiation and acquisition of self-renewing properties. In tumor cells, the YAP/TAZ–autophagy connection is key to sustain transformed traits and for acquisition of a cancer stem cell state by otherwise more benign cells. Mechanistically, YAP/TAZ promote autophagic flux by directly promoting the expression of Armus, a RAB7-GAP required for autophagosome turnover and whose add-back rescues autophagy in YAP/TAZ-depleted cells. These findings expand the influence of YAP/TAZ mechanotransduction to the control of autophagy and, vice versa, the role of autophagy in YAP/TAZ biology, and suggest a mechanism to coordinate transcriptional rewiring with cytoplasmic restructuring during cell reprogramming.

Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK–Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell’s environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies. 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.

Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumour suppression 1 . However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A–SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ 2 . Using a combination of gain- and loss-of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A–SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A–SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signalling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A–SWI/SNF, thereby preventing the formation of the ARID1A–SWI/SNF–YAP/TAZ complex, in favour of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signalling, and inhibition of ARID1A–SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis. 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.

In spite of tremendous advances made in the comprehension of mechanotransduction, implementation of mechanobiology assays remains challenging for the broad community of cell biologists. Hydrogel substrates with tunable stiffness are essential tool in mechanobiology, allowing to investigate the effects of mechanical signals on cell behavior. A bottleneck that slows down the popularization of hydrogel formulations for mechanobiology is the assessment of their stiffness, typically requiring expensive and sophisticated methodologies in the domain of material science. Here we overcome such barriers offering the reader protocols to set-up and interpret two straightforward, low cost and high-throughput tools to measure hydrogel stiffness: static macroindentation and micropipette aspiration. We advanced on how to build up these tools and on the underlying theoretical modeling. Specifically, we validated our tools by comparing them with leading techniques used for measuring hydrogel stiffness (atomic force microscopy, uniaxial compression and rheometric analysis) with consistent results on PAA hydrogels or their modification. In so doing, we also took advantage of YAP/TAZ nuclear localization as biologically validated and sensitive readers of mechanosensing, all in all presenting a suite of biologically and theoretically proven protocols to be implemented in most biological laboratories to approach mechanobiology.

Highly porous nanocomposite films were produced at room temperature from SiO 2 or TiO 2 –SiO 2 solutions synthesized by a sol–gel route in the presence of oxide nanoparticles. The photocatalytic behavior of titania-based films was controlled at the sol synthesis step, through three parameters: the relative molar concentration between polymeric and condensed silica, the reactivity of the hydrolysis step, and the relative molar concentration of the active component. The reported method allowed ample tuneability of film refractive index, an important parameter for the design of antireflective and multifunctional coatings. Superhydrophilic properties were demonstrated by the samples and, notably, retained for over 30 days. Experimentally mimicking accelerated surface pollution with olive oil and stearic acid, a strong correlation was found between residual organic contamination, quantified by integrating the film absorption FT-IR spectrum over the C–H n stretching area, and the measured water contact angle (WCA). Strategies for a fast surface cleaning and restoration of the superhydrophilic behavior via a mild oxidizing agent, based on UV exposure or immersion in a NaClO water solution, were investigated. High wettability can also be obtained through the control of the porosity. This effect has been termed nanowicking: the rapid infiltration of water in an interconnected porous network. Highlights Superhydrophilic highly porous nanocomposite films are realized through the effect of nanowicking. Films are produced by sol–gel at room temperature from SiO 2 or TiO 2 –SiO 2 in the presence of oxide nanoparticles. Ample tuneability of refractive index is achieved, allowing the design of antireflective and multifunctional coatings. Superhydrophilic properties are retained by the samples over 30 days. Fast surface cleaning and superhydrophilicity restoration is demonstrated UV exposure or immersion in a NaClO water solution.

Mechanical signals from the extracellular matrix are crucial in guiding cellular behavior. Two-dimensional hydrogel substrates for cell cultures serve as exceptional tools for mechanobiology studies because they mimic the biomechanical and adhesive characteristics of natural environments. However, the interdisciplinary knowledge required to synthetize and manipulate these biomaterials typically restricts their widespread use in biological laboratories, which may not have the material science expertise or specialized instrumentation. To address this, we propose a scalable method that requires minimal setup to produce 2D hydrogel substrates with independent modulation of the rigidity and adhesiveness within the range typical of natural tissues. In this method, norbornene-terminated 8-arm polyethylene glycol is stoichiometrically functionalized with RGD peptides and crosslinked with a di-cysteine terminated peptide via a thiol–ene click reaction. Since the synthesis process significantly influences the final properties of the hydrogels, we provide a detailed description of the chemical procedure to ensure reproducibility and high throughput results. We demonstrate examples of cell mechanosignaling by monitoring the activation state of the mechanoeffector proteins YAP/TAZ. This method effectively dissects the influence of biophysical and adhesive cues on cell behavior. We believe that our procedure will be easily adopted by other cell biology laboratories, improving its accessibility and practical application.

The need for a sensitive, selective, non-invasive and reversible fluorescent sensor for Zn 2+ monitoring is addressed in this work. A novel guest-host system is developed, including a Zn 2+ sensitive fluorescent probe, Zinpyr-1, embedded in a porous optically transparent hybrid film. The entrapped probe molecules are accessible and can interact with the external analyte. The immobilized Zinpyr-1 confirms its specificity and selectivity for Zn 2+ , as shown by sensing tests conducted in buffer solutions that mimic the ionic composition of biological media. The uniqueness of the developed sensor system lies in its reversibility, combined with a fast and selective response, allowing dynamic measurements of zinc concentrations in the 1 µM to 1 mM range within few tens of seconds. Unlike most Zn 2+ sensors, this system is a film-based sensor, making it an interesting minimally invasive tool for future studies on how live cells cultured on it dynamically regulate the Zn 2+ concentration under controlled physiological conditions.

Adaptive optics (AO) has transformed the understanding of biology and medicine by providing unprecedented access to their fundamental elements. This technology leverages techniques and strategies originally developed in astronomy to measure and correct optical aberrations. Herein, the development of a novel photo‐responsive optical material for AO applications is presented. The material consists of a photochromic film of a zirconia‐based hybrid organic–inorganic (HOI) matrix that incorporates up to 20% dithienylethene molecules. The exceptional photochromic properties and thermal stability of the photochromic component, combined with the remarkable optical properties, adjustable thickness, and high dye‐loading capacity of the HOI sol–gel matrix, enable the creation of a system optimized for refractive index modulation (Δn) under light exposure. Comprehensive evaluations of the photochromic material are conducted, analyzing changes in optical properties in response to varying light intensity and exposure time. Additionally, prototypes of focusable adaptive lenses specifically designed for operation in the near‐infrared spectrum are engineered, achieving a significant Δn of 0.0314, effectively minimizing efficiency losses attributable to material absorption. This study investigates a zirconia‐based hybrid organic–inorganic material incorporating dithienylethene molecules for adaptive optics. It offers excellent photochromic properties, thermal stability, and adjustable thickness, enabling effective refractive index modulation. Prototypes of adaptive lenses for the near‐infrared spectrum show Δn = 0.0314, minimizing absorption losses and improving efficiency.

Mechanical signals are increasingly recognized as overarching regulators of cell behaviour, controlling stemness, organoid biology, tissue development and regeneration. Moreover, aberrant mechanotransduction is a driver of disease, including cancer, fibrosis and cardiovascular defects. A central question remains how cells compute a host of biomechanical signals into meaningful biological behaviours. Biomaterials and microfabrication technologies are essential to address this issue. Here we review a large body of evidence that connects diverse biomaterial-based systems to the functions of YAP/TAZ, two highly related mechanosensitive transcriptional regulators. YAP/TAZ orchestrate the response to a suite of engineered microenviroments, emerging as a universal control system for cells in two and three dimensions, in static or dynamic fashions, over a range of elastic and viscoelastic stimuli, from solid to fluid states. This approach may guide the rational design of technological and material-based platforms with dramatically improved functionalities and inform the generation of new biomaterials for regenerative medicine applications.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.