General interests and key questions. We study how cells sense their environment and use this information to build and maintain tissues with specific form, size and function. We are also interested in how disruption of these homeostatic mechanisms leads to tumor formation, progression and metastasis.

Our work is mainly centered on the biology of YAP/TAZ, two closely related transcriptional regulators playing essential functions in tissue regeneration and cancer (reviewed in Zanconato et al., 2016).

1) We recently discovered a new reprogramming paradigm: activation of YAP/TAZ can turn differentiated cells of different types into their corresponding somatic stem cells. YAP or TAZ are molecular determinants by which differentiated cells acquire plasticity and stemness but respecting tissue barriers and lineage restrictions. The identification of YAP/TAZ as reprogramming factors for the somatic stem cell state raises interesting questions on their potential in regenerative medicine and in a number of physiological and pathological contexts in which cell plasticity of differentiated cells is in fact exploited in vivo (Panciera et al., 2016).

2) We recently contributed to the field of Mechanotransduction. Tissue architecture, mechanical forces and cell shape are overarching, yet poorly understood regulators of cell behavior. Key elements of these signals are cell-extracellular matrix (ECM) and cell-cell adhesions, cell polarity and the mechanical-induced distortion of the cytoskeleton that keep individual cells and whole tissues in a certain shape. Our work has shown that YAP and TAZ are central elements by which, in living systems, form dictates biological function. Indeed, YAP/TAZ are readers of "structural" signals and mediators of their effects. A central goal in our laboratory is to uncover the nature of cellular mechanotransduction systems in normal and pathologic contexts (Dupont et al., 2011; Aragona et al., 2013).

3) Regulation of YAP/TAZ. A key challenge is to understand how YAP/TAZ can serve as a hub, integrating Hippo signaling, cell mechanics and regulations from cell polarity, growth factors and other transcription factors.

Hippo signaling and cell polarity. We found that TAZ endows "cancer stemness" in mammary tumors. TAZ drives self-renewal and tumor initiation of cancer cells, and can turn non-stem cancer cells into cancer stem cells. In tumor cells, TAZ is activated by epithelial-mesenchymal transition (EMT) after loss of apico-basal polarity (an early step in EMT and a hallmark of cancer) through regulation of the Hippo pathway (Cordenonsi et al., 2011).

Wnt signaling. We found that YAP/TAZ are key nuclear effectors of Wnt signaling, through a mechanism involving the regulation of the cytoplasmic destruction complex (previously known to control ?-catenin stability). In vivo, by mouse genetic models, YAP/TAZ mediate the oncogenic effects of aberrant Wnt signaling caused by loss of the APC (Azzolin et al., 2012; Azzolin et al., 2014).

YAP/TAZ targets. Despite their biological potency, the function of YAP/TAZ as transcriptional regulators remains poorly understood. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping (Zanconato et al., 2015).

Our approach to these goals entails both hypothesis-driven and data-driven investigations and combines an interdisciplinary set of expertise, ranging from molecular, biochemical and cell biological tools to animal models, tissue engineering, material science and "omic" approaches.