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Dive into the research topics where Silvio Bicciato is active.

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Featured researches published by Silvio Bicciato.


Nature | 2011

Role of YAP/TAZ in mechanotransduction

Sirio Dupont; Leonardo Morsut; Mariaceleste Aragona; Elena Enzo; Stefano Giulitti; Michelangelo Cordenonsi; Francesca Zanconato; Jimmy le Digabel; Mattia Forcato; Silvio Bicciato; Nicola Elvassore; Stefano Piccolo

Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.


Journal of Clinical Investigation | 2006

Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells

Giovanna Gallina; Luigi Dolcetti; Paolo Serafini; Carmela De Santo; Ilaria Marigo; Mario P. Colombo; Giuseppe Basso; Frank Brombacher; Ivan Borrello; Paola Zanovello; Silvio Bicciato; Vincenzo Bronte

Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.


Cell | 2011

The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells

Michelangelo Cordenonsi; Francesca Zanconato; Luca Azzolin; Mattia Forcato; Antonio Rosato; Chiara Frasson; Masafumi Inui; Marco Montagner; Anna Parenti; Alessandro Poletti; Maria Grazia Daidone; Sirio Dupont; Giuseppe Basso; Silvio Bicciato; Stefano Piccolo

Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.


Cell | 2009

A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis

Maddalena Adorno; Michelangelo Cordenonsi; Marco Montagner; Sirio Dupont; Christine Wong; Byron Hann; Aldo Solari; Sara Bobisse; Maria Rondina; Vincenza Guzzardo; Anna Parenti; Antonio Rosato; Silvio Bicciato; Allan Balmain; Stefano Piccolo

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.


Cell | 2010

A MicroRNA Targeting Dicer for Metastasis Control

Graziano Martello; Antonio Rosato; Francesco Ferrari; Andrea Manfrin; Michelangelo Cordenonsi; Sirio Dupont; Elena Enzo; Vincenza Guzzardo; Maria Rondina; Thomas Spruce; Anna Parenti; Maria Grazia Daidone; Silvio Bicciato; Stefano Piccolo

Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery. In human breast cancer, high levels of miR-103/107 are associated with metastasis and poor outcome. Functionally, miR-103/107 confer migratory capacities in vitro and empower metastatic dissemination of otherwise nonaggressive cells in vivo. Inhibition of miR-103/107 opposes migration and metastasis of malignant cells. At the cellular level, a key event fostered by miR-103/107 is induction of epithelial-to-mesenchymal transition (EMT), attained by downregulating miR-200 levels. These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis.


Immunity | 2010

Tumor-Induced Tolerance and Immune Suppression Depend on the C/EBPβ Transcription Factor

Ilaria Marigo; Erika Bosio; Samantha Solito; Circe Mesa; Audry Fernández; Luigi Dolcetti; Stefano Ugel; Nada Sonda; Silvio Bicciato; Erika Falisi; Fiorella Calabrese; Giuseppe Basso; Paola Zanovello; Emanuele Cozzi; Susanna Mandruzzato; Vincenzo Bronte

Tumor growth is associated with a profound alteration in myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). We showed that among factors produced by various experimental tumors, the cytokines GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of CD8(+) T cells and allow long term acceptance of pancreatic islet allografts. Cytokines inducing MDSCs acted on a common molecular pathway and the immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on the C/EBPbeta transcription factor. Adoptive transfer of tumor antigen-specific CD8(+) T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBPbeta in the myeloid compartment, suggesting that C/EBPbeta is a critical regulator of the immunosuppressive environment created by growing cancers.


Nature Immunology | 2011

Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells

Maria Teresa Pallotta; Ciriana Orabona; Claudia Volpi; Carmine Vacca; Maria Laura Belladonna; Roberta Bianchi; Giuseppe Servillo; Cinzia Brunacci; Mario Calvitti; Silvio Bicciato; Emilia Maria Cristina Mazza; Louis Boon; Fabio Grassi; Maria C. Fioretti; Francesca Fallarino; Paolo Puccetti; Ursula Grohmann

Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.


Cell | 2014

YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response

Luca Azzolin; Tito Panciera; Sandra Soligo; Elena Enzo; Silvio Bicciato; Sirio Dupont; Silvia Bresolin; Chiara Frasson; Giuseppe Basso; Vincenza Guzzardo; Ambrogio Fassina; Michelangelo Cordenonsi; Stefano Piccolo

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.


Nature | 2014

Aryl hydrocarbon receptor control of a disease tolerance defence pathway

Alban Bessede; Marco Gargaro; Maria Teresa Pallotta; Davide Matino; Giuseppe Servillo; Cinzia Brunacci; Silvio Bicciato; Emilia Maria Cristina Mazza; Antonio Macchiarulo; Carmine Vacca; Rossana G. Iannitti; Luciana Tissi; Claudia Volpi; Maria Laura Belladonna; Ciriana Orabona; Roberta Bianchi; Tobias V. Lanz; Michael Platten; Maria Agnese Della Fazia; Danilo Piobbico; Teresa Zelante; Hiroshi Funakoshi; Toshikazu Nakamura; David Gilot; Michael S. Denison; Gilles J. Guillemin; James B. DuHadaway; George C. Prendergast; Richard Metz; Michel Geffard

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.


Cell | 2012

Role of TAZ as Mediator of Wnt Signaling

Luca Azzolin; Francesca Zanconato; Silvia Bresolin; Mattia Forcato; Giuseppe Basso; Silvio Bicciato; Michelangelo Cordenonsi; Stefano Piccolo

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.

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