Controlled production of cytokines and growth factors, leading to the activation of specific signalling pathways and to the modulation of gene expression, is essential for life. However, aberrant cytokines/growth factors production or altered regulation of their signalling and/or of the activity of the downstream transcription factors are at the basis of many pathological conditions including chronic inflammation, auto-immunity and oncogenesis. The laboratory focuses in particular on the axis between the pro-inflammatory cytokine IL-6 and the transcription factor STAT3 at the crossroads between inflammation, immunity and cancer, aiming at characterizing its involvement in both physiological and pathological conditions.Main ongoing research projects1) Mechanisms of oncogenesis by aberrantly active Stat3. In recent years we have demonstrated that constitutively active STAT3 can cooperate with oncogenes such as the HER2/Neu to confer agressive features to breast tumors and support metastasis formation (Barbieri et al., 2010). Moreover, we have shown that aberrantly active STAT3 can regulate energy metabolism and mitochondrial activity and can act as a first hit in tumor transformation, shedding light on its well known central role in inflammation-induced tumorigenesis (Demaria et al., 2010& 2012). Present projects along these lines include:1a) STAT3-dependent and independent mechanisms of enhanced cell movement and EMT via the action of specific microRNAs1b) Canonical and non-canonical STAT3-mediated regulation of calcium signaling, respiratory metabolism and apoptosis/autophagy.1c) STAT3-dependent and independent mechanisms of cross-talk between tumor cells and Cancer Associated Fibroblasts1d) Synergistic cross-talk between the Wnt/PCP and STAT3 pathways in basal-like breast cancer2) Novel mechanisms of STAT3-mediated ES cells totipotency via the transcriptional control of specific long non-coding (linc) RNAs. We have identified a subset of STAT3-dependent ES cell-specific lincRNAs and want to characterize ther mechanism of action and their implications in tumorigenesis and in the generation of induced pluripotent stem cells.3) Role of the axis IL-6/STAT3/complement in regulating chronic inflammation and heart auto-immunity. We have recently shown that STAT3 is both sufficient and necessary to trigger the onset of immune-mediated myocarditis, activating a feed-forward loop involving enhanced IL-6 signalling and complement factors production in the liver (Camporeale, Marino et al., EMBO Mol. Med. 2013). Current reserch aims at i) identifying the role of complement factors in determining the onset and outcome of auto-immune myocardiotis in both mouse models and human patients and ii) testing several STAT3 and Complement inhibitors as therapeutic approaches, in the attempot to find suitable treatments for virus-positive patients, not amenable to immune suppression.
Il laboratorio si focalizza sull’analisi delle attivita’ biologiche del fattore di trascrizione STAT3, e in particolare sulla comprensione dei meccanismi tramite i quali STAT3 agisce come un oncogene, mediando la causalita’ tra infiammazione e tumore e causando l’insorgenza di malattie quali la miocardite autoimmunitaria. In pareticolare, le ricerche piu’ recenti si incentrano su: i) indagare il ruolo delle forme diversamente fosforilate di STAT3 nel controllo del metabolismo energetico delle cellule, sia normali che trasformate, e come queste attivita’ possano controllare fenomeni fondamentali come l’apoptosi e l’autofagia; ii) analizzare il ruolo di diversi nuovi bersagli di STAT3 che abbiamo identificato recentemente nel controllare l’infiammazione, la staminalita’, l’omeostasi della pelle e la crescita invasiva dei tumori mammari; iii) definire le interazioni funzionali tra la via di segnalazione di STAT3 e quella di Wnt nei tumori mammari, attraverso la regolazione del comune gene bersaglio RhoU; iv) definire il ruolo dell’infiammazione di fase acuta e dell’attivazione dell’asse IL-6/STAT3 nel fegato nella progressione della miocardite autoimmunitaria verso l’insufficienza cardiaca. A questo proposito sono in atto studi volti a definire nuovi approcci diagnostici e soprattutto terapeutici.
Dr. Annalisa Camporeale (post-doctoral fellow)
Dr. Lidia Avalle (post-doctoral fellow)
Dr. Francesca Marino (post-doctoral fellow)
Dr. Emanuele Monteleone (post-doctoral fellow)
Dr. Aurora Savino (graduate fellow)
Miss Laura Raggi (undergraduate student)
Miss Paola Corrieri (undergraduate student)
Mr Emanuele Epifani (undergraduate student)