Our research unit investigates the molecular and cellular processes involved in carcinogenesis and tumor progression with the goal of identifying novel molecular targets for specific therapies and overcome drug resistance. To this end we use a multidisciplinary panel of techniques ranging from cellular biology and biochemistry to advanced single molecule fluorescence microscopy and correlative fluorescence/electron microscopy.
- Modulation of ErbB receptors signaling to drive cancer cell fate. ErbB is a family of membrane receptors, classically thought to promote cell survival and cell growth and whose activity often is exacerbated in solid tumors. A member of this family, ErbB2, is over-expressed in 20% of breast cancers, and ErbB2 positive tumors are generally more aggressive than Erbb2 negative ones. Several antitumoral drugs target ErbB2 to arrest tumor cell growth, but tumor cells can adapt to resist to these therapies. In our lab we have identified a novel mechanism to modulate the ErbB2 signaling, that could be in principle used to oppose cancer cell resistance to ErbB2-targetted therapies.
- Characterization of transcription factors with oncogenic or tumor-suppression potential at the single molecule level. We have pioneered a single- molecule approach to quantify the interaction kinetics between nuclear proteins (transcription factors) and their binding sites on DNA in living cells, and we are currently applying it to dissect the causes that underlie activation and inactivation of those transcription factors that act as tumor suppressors or oncogenes in cancer settings. We first characterized the single molecule behavior of the tumor-suppressor p53 (a fundamental transcription factor fundamental for maintaining genomic integrity and frequently mutated/inactivated in cancer). We are now applying our technique to test therapeutic strategies that could be used to reactivate p53 in breast cancer and in neuroblastoma.
- Dissecting the translation reprogramming mechanisms as a targetable vulnerability in breast cancer. Multiple microenvironmental cues, such as nutrients and oxygen deprivation and inflammatory cytokines, have been implicated in driving cancer metastatic potential, metabolic rewiring and drug resistance. We recently found an evolutionarily conserved mechanism by which the cancer cell responds to microenvironmental stimuli activating a stress response signalling cascade converging on peIF2a-ATF4 axis. This adaptive response provides the cell with a selective advantage in terms of survival and proliferation. Metabolic stress above threshold leads to maladaptive response resulting in activation of apoptotic pathways. The fine-tuning of peIF2a-ATF4 stimulation could tip the cell fate from proliferative to apoptotic. Since cancer cells exploit this conserved mechanism to survive, bypass senescence, and metastasize, we want to exploit this vulnerability to harness breast cancer.
Caldieri G, Barbieri E, Nappo G, Raimondi A, Bonora M, Conte A, Verhoef LGGC, Confalonieri S, Malabarba MG, Bianchi F, Cuomo A, Bonaldi T, Martini E, Mazza D, Pinton P, Tacchetti C, Polo S, Di Fiore PP, Sigismund S. Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis. Science. 356:617-624, 2017
Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, Pellegrini L, Signorato V, Olivetto F, Pastorino S, Nasu M, Napolitano A, Gaudino G, Morris P, Sakamoto G, Ferris LK, Danese A, Raimondi A, Tacchetti C, Kuchay S, Pass HI, Affar EB, Yang H, Pinton P, Carbone M. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature. 546:549-553, 2017
Loffreda A, Jacchetti E, Antunes S, Rainone P, Daniele T, Morisaki T, Bianchi ME, Tacchetti C, Mazza D. Live-cell p53 single-molecule binding is modulated by C-terminal acetylation and correlates with transcriptional activity. Nat Commun. 8:313, 2017
Bagnato P, Castagnino A, Cortese K, Bono M, Grasso S, Bellese G, Daniele T, Lundmark R, Defilippi P, Castagnola P, Tacchetti C. Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells. Oncotarget. 8:60109-60122, 2017
Missiroli S, Bonora M, Patergnani S, Poletti F, Perrone M, Gafà R, Magri E, Raimondi A, Lanza G, Tacchetti C, Kroemer G, Pandolfi PP, Pinton P, Giorgi C. PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development. Cell Report 16:2415–27, 2016
Daniele T, Hurbain I, Vago R., Casari G., Raposo G., Tacchetti C., Schiaffino MV. Mitochondria and Melanosomes Establish Physical Contacts Modulated by Mfn2 and Involved in Organelle Biogenesis. Curr. Biol. 24:393-403, 2014
Cortese K., M. T. Howes, R. Lundmark, E. Tagliatti, P. Bagnato, A. Petrelli, M. Bono, H. T. McMahon, R. G. Parton, C. Tacchetti. The HSP90 inhibitor Geldanamycin perturbs endosomal structure and drives recycling ErbB2 and Transferrin to modified MVBs/lysosomal compartments. Mol. Biol. Cell 24:129-144, 2013
Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247-51,2010
Vicidomini G., Gagliani M.C., Canfora M., Cortese K., Frosi F., Santangelo C., Di Fiore P.P., Boccacci P., Diaspro A., and Tacchetti C. High data output automated 3D correlative light-electron microscopy method. Traffic 9:1828-1838, 2008
Puri C., Tosoni D., Comai R., Rabellino A., Segat D., Caneva F., Luzzi P., Agostini M., Di Fiore P.P, and Tacchetti C. Relationships between EGFR signaling-competent and endocytosis-competent membrane microdomains. Mol. Biol. Cell. 16:2704-2718, 2005
Valabrega C., Montemurro F., Sarotto I., Petrelli A., Rubini P., Tacchetti C., Aglietta M., Comoglio P.M., and Giordano S. TGFα expression impairs Trastuzumab-induced HER2 down-regulation. Oncogene 24:3002-10, 2005
Sigismund S., Woelk T., Puri C., Maspero E., Tacchetti C., Transidico P., Di Fiore P.P., and Polo S. Clathrin-independent endocytosis of ubiquitinated cargos. P. Natl. Acad. Sci. USA 102:2760-65, 2005
Tosoni D., Puri C., Confalonieri S., Salcini A.E., De Camilli P., Tacchetti C., and Di Fiore P.P. TTP specifically regulates the internalization of the transferrin receptor. Cell 123:875-88, 2005
Croce A., Cassata G., Disanza A., Gagliani M.C., Tacchetti C., Malabarba M.G., Carlier M-F., Scita G., Baumeister R., and Di Fiore P.P. A novel actin barbed end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nature Cell Biol. 6:1173-9, 2004
Segat D., Comai R., Di Marco E., Strangio A., Cancedda R., Franzi A.T., and Tacchetti C. Integrins a6Ab1 and a6Bb1 promote different stages of chondrogenic cell differentiation. J. Biol. Chem. 277:31612-31622, 2002