Stefano Piccolo

Arizona State University, Mesa, AZ, United States

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Publications (70)1137.7 Total impact

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    ABSTRACT: YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. 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. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.
    Nature Cell Biology 08/2015; DOI:10.1038/ncb3216 · 20.06 Impact Factor
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    ABSTRACT: Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-β and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.Oncogene advance online publication, 15 June 2015; doi:10.1038/onc.2015.176.
    Oncogene 06/2015; DOI:10.1038/onc.2015.176 · 8.56 Impact Factor
  • Stefano Piccolo · Eduard Batlle
    Current Opinion in Cell Biology 12/2014; 31:v-vi. DOI:10.1016/ · 8.74 Impact Factor
  • Stefano Piccolo · Sirio Dupont · Michelangelo Cordenonsi
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    ABSTRACT: The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key for the growth of whole organs, for amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and for cell proliferation. In tumors, YAP/TAZ can reprogram cancer cells into cancer stem cells and incite tumor initiation, progression and metastasis. As such, YAP/TAZ are appealing therapeutic targets in cancer and regenerative medicine. Just like the function of YAP/TAZ offers a molecular entry point into the mysteries of tissue biology, their regulation by upstream cues is equally captivating. YAP/TAZ are well known for being the effectors of the Hippo signaling cascade, and mouse mutants in Hippo pathway components display remarkable phenotypes of organ overgrowth, enhanced stem cell content and reduced cellular differentiation. YAP/TAZ are primary sensors of the cell's physical nature, as defined by cell structure, shape and polarity. YAP/TAZ activation also reflects the cell "social" behavior, including cell adhesion and the mechanical signals that the cell receives from tissue architecture and surrounding extracellular matrix (ECM). At the same time, YAP/TAZ entertain relationships with morphogenetic signals, such as Wnt growth factors, and are also regulated by Rho, GPCRs and mevalonate metabolism. YAP/TAZ thus appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context.
    Physiological Reviews 10/2014; 94(4):1287-1312. DOI:10.1152/physrev.00005.2014 · 29.04 Impact Factor
  • Stefano Piccolo
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    ABSTRACT: Stefano Piccolo looks back at the life and research of his friend and colleague Yoshiki Sasai.
    Development 08/2014; 141(19). DOI:10.1242/dev.116509 · 6.27 Impact Factor
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    ABSTRACT: The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression.
    Cell 06/2014; 158(1). DOI:10.1016/j.cell.2014.06.013 · 33.12 Impact Factor
  • Stefano Piccolo
    Seminars in Cell and Developmental Biology 05/2014; 32. DOI:10.1016/j.semcdb.2014.04.033 · 5.97 Impact Factor
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    ABSTRACT: The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate-YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
    Nature Cell Biology 03/2014; 16(4). DOI:10.1038/ncb2936 · 20.06 Impact Factor
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    ABSTRACT: Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.Oncogene advance online publication, 17 February 2014; doi:10.1038/onc.2014.5.
    Oncogene 02/2014; 34(6). DOI:10.1038/onc.2014.5 · 8.56 Impact Factor
  • Stefano Piccolo
    Nature 12/2013; 504(7479):223-225. DOI:10.1038/504223a · 42.35 Impact Factor
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    ABSTRACT: Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate myostatin lead to excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.
    Nature Genetics 09/2013; 23(9-10). DOI:10.1038/ng.2772 · 29.65 Impact Factor
  • Stefano Piccolo
    Differentiation 09/2013; 86(3). DOI:10.1016/j.diff.2013.08.001 · 2.84 Impact Factor
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    ABSTRACT: Key cellular decisions, such as proliferation or growth arrest, typically occur at spatially defined locations within tissues. Loss of this spatial control is a hallmark of many diseases, including cancer. Yet, how these patterns are established is incompletely understood. Here, we report that physical and architectural features of a multicellular sheet inform cells about their proliferative capacity through mechanical regulation of YAP and TAZ, known mediators of Hippo signaling and organ growth. YAP/TAZ activity is confined to cells exposed to mechanical stresses, such as stretching, location at edges/curvatures contouring an epithelial sheet, or stiffness of the surrounding extracellular matrix. We identify the F-actin-capping/severing proteins Cofilin, CapZ, and Gelsolin as essential gatekeepers that limit YAP/TAZ activity in cells experiencing low mechanical stresses, including contact inhibition of proliferation. We propose that mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts, setting responsiveness to Hippo, WNT, and GPCR signaling.
    Cell 08/2013; 154(5). DOI:10.1016/j.cell.2013.07.042 · 33.12 Impact Factor
  • Stefano Piccolo · Elena Enzo · Marco Montagner
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    ABSTRACT: Metastasis is the most significant cause of cancer-associated morbidity and mortality but remains poorly understood. Recent work revealed that metastasis of aggressive triple-negative breast cancers is suppressed by Sharp1, a factor that promotes degradation of hypoxia-inducible factors (HIF) and blunts HIF-induced malignant cell behavior. Cancer Res; 73(16); 1-4. ©2013 AACR.
    Cancer Research 08/2013; 73(16). DOI:10.1158/0008-5472.CAN-13-0962 · 9.28 Impact Factor
  • Stefano Piccolo · Michelangelo Cordenonsi · Sirio Dupont
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    ABSTRACT: The evolution of a solid tumor is fueled by genetic aberrations. Yet, the tumor environment often dominates over the effects of genetics: normal tissues have powerful tumor suppressive properties that constantly tame or eliminate cells carrying transforming mutations. Critical elements of such suppressive microenvironment are structural characteristics of normal cells and tissues, such as cell polarity, attachment to the extracellular matrix (ECM) and epithelial organization. Once these tissue-level checkpoints have been overcome, tumor growth is enhanced by recruitment of stromal cells and remodeling of the ECM. Genetic inactivation in mouse models indicates the Hippo pathway as fundamental inhibitor of organ growth during development and as critical tumor suppressor in epithelial tissues such as the liver, the skin and ovaries, and in soft tissues. At the centerpiece of this pathway lie two related transcriptional coactivators, YAP and TAZ, that promote tissue proliferation, the self-renewal of normal and cancer stem cells, and incite metastasis. Strikingly, YAP and TAZ are controlled by the same architectural features that first inhibit and then foster cancer growth, such as ECM elasticity, cell shape and epithelial-to-mesenchymal transition (EMT). These findings open unexpected opportunities for the development of new cancer therapeutics targeting key YAP/TAZ regulatory inputs such as Wnt signaling, cytoskeletal contractility, GPCRs or YAP/TAZ-regulated transcription.
    Clinical Cancer Research 06/2013; 19(18). DOI:10.1158/1078-0432.CCR-12-3172 · 8.19 Impact Factor
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    ABSTRACT: Triple negative breast cancers, which are defined by lack of expression of estrogen, progesterone, or HER2 receptors, represent approximately 15% of all breast cancers, although they account for a much higher proportional of breast cancer mortality. This is due both to their innate aggressive biological characteristics, but also to lack of effective therapies. Conventional chemotherapy is currently the only treatment option, thus there is a critical need to find new and effective targeted therapies in this disease. While investigation of agents such as poly (ADP-ribose) polymerase (PARP) inhibitors and EGFR inhibitors continues, results from recent clinical trials indicate that these therapies are not as active in sporadic triple negative breast cancers as initially hoped. It is important therefore to consider other emerging therapeutic agents. Mutation in p53 is found in the vast majority of triple negative breast cancers, and as such is a target of particular interest. Within this review, several agents with potential activity against aberrant p53 signaling have been considered, as a novel approach to finding an effective targeted therapy for this aggressive breast cancer subtype.
    Cancer Treatment Reviews 01/2013; 39(5). DOI:10.1016/j.ctrv.2012.12.001 · 6.47 Impact Factor
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    ABSTRACT: Wnt growth factors are fundamental regulators of cell fate, but how the Wnt signal is translated into biological responses is incompletely understood. Here, we report that TAZ, a biologically potent transcriptional coactivator, serves as a downstream element of the Wnt/β-catenin cascade. This function of TAZ is independent from its well-established role as mediator of Hippo signaling. In the absence of Wnt activity, the components of the β-catenin destruction complex-APC, Axin, and GSK3-are also required to keep TAZ at low levels. TAZ degradation depends on phosphorylated β-catenin that bridges TAZ to its ubiquitin ligase β-TrCP. Upon Wnt signaling, escape of β-catenin from the destruction complex impairs TAZ degradation and leads to concomitant accumulation of β-catenin and TAZ. At the genome-wide level, a substantial portion of Wnt transcriptional responses is mediated by TAZ. TAZ activation is a general feature of Wnt signaling and is functionally relevant to mediate Wnt biological effects.
    Cell 12/2012; 151(7). DOI:10.1016/j.cell.2012.11.027 · 33.12 Impact Factor
  • Stefano Piccolo
    Nature medicine 10/2012; 18(10):1463-5. DOI:10.1038/nm.2955 · 28.05 Impact Factor
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    ABSTRACT: The Spemann organizer stands out from other signaling centers of the embryo because of its broad patterning effects. It defines development along the anteroposterior and dorsoventral axes of the vertebrate body, mainly by secreting antagonists of growth factors. Qualitative models proposed more than a decade ago explain the organizer's region-specific inductions (i.e., head and trunk) as the result of different combinations of antagonists. For example, head induction is mediated by extracellular inhibition of Wnt, BMP, and Nodal ligands. However, little is known about how the levels of these antagonists become harmonized with those of their targets and with the factors initially responsible for germ layers and organizer formation, including Nodal itself. Here we show that key ingredients of the head-organizer development, namely Nodal ligands, Nodal antagonists, and ADMP ligands reciprocally adjust each other's strength and range of activity by a self-regulating network of interlocked feedback and feedforward loops. A key element in this cross-talk is the limited availability of ACVR2a, for which Nodal and ADMP must compete. By trapping Nodal extracellularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity. The system self-regulates because ADMP/ACVR2a/Smad1 signaling in turn represses the expression of the Nodal antagonists, reestablishing the equilibrium. In sum, this work reveals an unprecedented set of interactions operating within the organizer that is critical for embryonic patterning.
    Proceedings of the National Academy of Sciences 09/2012; 109(38):15354-9. DOI:10.1073/pnas.1203000109 · 9.81 Impact Factor
  • Georg Halder · Sirio Dupont · Stefano Piccolo
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    ABSTRACT: The physical and mechanical properties of the cellular microenvironment regulate cell shape and can strongly influence cell fate. How mechanical cues are sensed and transduced to regulate gene expression has long remained elusive. Recently, cues from the extracellular matrix, cell adhesion sites, cell shape and the actomyosin cytoskeleton were found to converge on the regulation of the downstream effectors of the Hippo pathway YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) in vertebrates and Yorkie in flies. This convergence may explain how mechanical signals can direct normal and pathological cell behaviour.
    Nature Reviews Molecular Cell Biology 08/2012; 13(9):591-600. DOI:10.1038/nrm3416 · 36.46 Impact Factor

Publication Stats

5k Citations
1,137.70 Total Impact Points

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  • 2012
    • Arizona State University
      • School of Life Sciences
      Mesa, AZ, United States
  • 1993–2012
    • University of Padova
      • Department of Biomedical Sciences - DSB
      Padua, Veneto, Italy
  • 2005–2010
    • It-Robotics
      Vicenza, Veneto, Italy
  • 2008
    • Memorial Sloan-Kettering Cancer Center
      • Hematology Service
      New York, New York, United States