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Ischemic heart diseases and cancers are leading causes of death worldwide. On one hand, cancer cells undergo deregulated proliferation. Conversely, the inability of cardiac muscle cells (cardiomyocytes) to re-enter into the cell cycle and proliferate is a major reason behind the lack of cardiac regenerative ability in adult mammals.

Our lab aims to understand molecular mechanisms driving cell differentiation and proliferation in these two diseases, in order to develop novel strategies to more effectively “block” cancer cells and to “unlock” the cardiac regenerative potential.

Furthermore, we are carrying out studies simultaneously focusing on tumour growth and heart function, in order to develop therapeutic strategies for the emerging problem of cardiotoxicity of anti-cancer therapies, which is responsible for a poor quality of life and reduced survival of cancer patients, regardless of the oncologic prognosis.

Research

Cardiac regeneration

Severe cardiac injuries, such those induced by myocardial infarction (also known as heart attack), lead to a significant loss of cardiac muscle cells (cardiomyocytes), which are replaced by a non-contractile fibrotic scar at the infarct site. The loss of contractile cells and the inability of the adult mammalian heart to regenerate is a major cause of cardiac dysfunction and heart failure.
Stimulating the very low intrinsic proliferation rate of cardiomyocytes is a promising strategy for cardiac repair in patients with heart failure. It is therefore imperative to better understand the signalling pathways that promote cardiomyocyte proliferation.
We previously dissected important molecular mechanisms governing tissue renewal/regeneration in different tissues (Nature Cell Biology, 2015; Cell Cycle, 2015; Nature Immunology 2012; Nature Immunology 2011JCI; 2013, Leukemia, 2013). In the cardiac tissue we recently demonstrated that the co-receptor ERBB2 is necessary for the proliferative response induced by the growth factor Neuregulin 1 (NRG1) during embryonic and neonatal stages. Further, we unveiled that cardiac ERBB2 levels decline soon after birth in mice, as part of the mechanism that leads to cardiomyocyte terminal differentiation and cell cycle withdrawal, and, consequently, loss of cardiac regenerative ability. By employing transgenic models, we demonstrated that a transient induction of ERBB2 signalling is sufficient to promote cardiomyocyte cell dedifferentiation and proliferation and to trigger a robust regenerative response following myocardial infarction in adult mice (Nature Cell Biology, 2015; Cell Cycle, 2015).
We are currently exploring strategies for modulation of Erbb2 signalling, in order to develop novel regenerative medicine approaches in the adult mammalian heart based on renewal of endogenous cardiomyocytes.

Cancer & Cardiotoxicity

Cancer cell biology has played a crucial role in elucidating the molecular mechanisms by which oncogenic pathways sustain malignant behaviours and in identifying targets for anti-cancer drugs. Among them, growth factor receptors of ERBB family (composed by EGFR/ERBB1, ERBB2, ERBB3 and ERBB4) play major roles in a variety of cancer types. ERBB2 (also known as HER2) is the only ERBB receptor family member unable to bind ligands. However it is the preferential partner for hetero-dimerization, powerfully enhancing and diversifying the downstream signalling pathway. Erbb2 is overexpressed in approximately 25-30% of breast carcinomas and in several other cancer types. These past decades have witnessed the impressive advances in the comprehension of the driving role of the ERBB2 gene in cancer cell survival, proliferation, migration and resistance to chemotherapies. Pharmacological inhibition of ERBB2, via monoclonal antibodies or tyrosine kinase inhibitors, represents a milestone in cancer treatment. Unfortunately cardio-toxicity is a serious side-effect of anti-HER2 therapies.

We previously contributed at dissecting the role, signalling and crosstalks of ERBB receptors in solid tumors (Nature Communication, 2014; Oncotarget 2016; Seminars in Cell and Developmental Biology, 2016Plos One, 2013)  as well as within the heart (Nature Cell Biology, 2015; Cell Cycle, 2015). By elucidating the molecular details of the ligand-receptor signalling axis NRGs-ERBBs in breast cancers and in the cardiac tissues, we aim at improving the efficacy and safety of HER2-targeted anti-cancer therapies.

Publications

Selected Publications

Gelfo V, Rodia MT, Pucci M, Dall’Ora M, Santi S, Solmi R, Roth L, Lindzen M, Bonafè M, Bertotti A, Caramelli E, Lollini PL, Trusolino L, Yarden Y, D’Uva G*, Lauriola M.
A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors.
Oncotarget, 2016
(* co-last author)


D’Uva G and Lauriola M.
Towards the emerging crosstalk: ERBB family and steroid hormones.
Seminars in Cell and Developmental Biology, 2016
(* co-correponding author)


D’Uva G and Tzahor E.
The key roles of ERBB2 in cardiac regeneration.
Cell Cycle, 2015


D’Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, Weisinger K, Bassat E, Rajchman D, Yifa O, Lysenko M, Konfino T, Hegesh J, Brenner O, Neeman M, Yarden Y, Leor J, Sarig R, Harvey RP and Tzahor E.
ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.
Nature Cell Biology, 2015

Awards and honours:
• commented in Nature: Regenerative biology: Neuregulin 1 makes heart muscle
• commented in Science: New hope for heart attack sufferers?
• highlighted in Nature Reviews Drug Discovery: Research Highlights
• highlighted by National Association for Biomedical Research (NABR: The Essential Need for Animals in Medical Research as an important example of biomedical research that justifies the essential need for animals in medical research.

International media coverage, including The Guardian, The Sydney Morning Herald, SKY NEWS, The Times of Israel, Il Sole 24 Ore and La Repubblica


Lauriola M, Enuka Y, Zeisel A, D’Uva G, Roth L, Sharon-Sevilla M, Lindzen M, Sharma K, Nevo N, Feldman M, Carvalho S, Cohen-Dvashi H, Kedmi M, Ben-Chetrit N, Chen A, Solmi R, Wiemann S, Schmitt F, Domany E and Yarden Y.
Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment.
Nature Communications, 2014

International media coverage, including Time, Daily Mail, Forbes and Huffington Post


D’Uva G*, Bertoni S, Lauriola M, De Carolis S, Pacilli A, D’Anello L, Santini D, Taffurelli M, Ceccarelli C, Yarden Y, Montanaro L, Bonafé M and Storci G.
Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia.
PLoS One, 2013
(* co-corresponding author)


Kollet O*, Vagima Y*, D’Uva G, Golan K, Canaani J, Itkin T, Gur-Cohen S, Kalinkovich A, Caglio G, Medaglia C, Ludin A, Lapid K, Shezen E, Neufeld-Cohen A, Varol D, Chen A and Lapidot T.
Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors.
Leukemia, 2013
(*equal contribution)


Lapid K, Itkin T, D’Uva G, Ovadya Y, Ludin A, Caglio G, Kalinkovich A, Golan K, Porat Z, Zollo M and Lapidot T.
GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement.
Journal of Clinical Investigation, 2013


Ludin A, Itkin T, Gur-Cohen S, Mildner A, Shezen E, Golan K, Kollet O, Kalinkovich A, Porat Z, D’Uva G, Schajnovitz A, Voronov E, Brenner DA, Apte RN, Jung S and Lapidot T.
Monocytes-macrophages that express α-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow.
Nature Immunology, 2012


Schajnovitz A, Itkin T, D’Uva G, Kalinkovich A, Golan K, Ludin A, Cohen D, Shulman Z, Avigdor A, Nagler A, Kollet O, Seger R, Lapidot T.
CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions.
Nature Immunology, 2011

Awards and honours:
• selected for the cover of Nature Immunology (May 2011)
• commented in Nature Immunology – News and Views


Full publication list available here

Patents

United States Patent Application 20160326250 published on 11/10/2016, filed on 5 May 2016, application number 15/147178 – “METHODS, KITS AND DEVICES FOR PROMOTING CARDIAC REGENERATION” – TZAHOR E, D’UVA GM, SARIG R, AHARONOV A, HARVEY RP and UMANSKY KB

Press and media

PRESS AND WEBSITES

29.04.2017 – Giannella Channel: Cervelli d’Italia, unitevi e rientrate. Un appello, affidato a Giannella Channel, dal cardiologo Gabriele D’Uva


28.04.2017 – Gli Stati Generali: Gabriele D’Uva, l’italiano grazie al quale rigenereremo i cuori infartuati


15.04.2017 – Giannella Channel: E’ arrivato in Italia il medico che ha scoperto come restaurare un cuore infranto


01.07.2015 – Sergio Lombroso Program: Borsisti del Sergio Lombroso Program


29.04.2015 – HealthCanal: HEART ATTACK BREAKTHROUGH


28.04.2015 – Salzburger Nachrichten: Krebs-Wachstumsrezeptor steuert Regeneration von Herzzellen


23.04.2015 – RaiNews: Un gene ripara-cuore


23.04.2015 – La Repubblica: Trovato un gene per riparare il cuore dopo un infarto


20.04.2015 – Giannella channel: È italiano il medico che ha scoperto come riparare un cuore infranto


19.04.2015 – Corriere di Bologna: Gabriele, il ricercatore che ha riacceso il cuore e vuol tornare in Italia


15.04.2015 – The Algemeiner: Israeli Scientists Regenerate Heart Cells in Revolutionary Discovery


14.04.2015 – Horizon 2020 projects: ERC-funded research sees mouse heart cells renewed


14.04.2015 – Israel Hayom: Israeli scientists make revolutionary discovery, regenerated heart cells


14.04.2015 – Corriere del mezzogiorno: Studio il cuore, sogno l’Italia


14.04.2015 – Farmacia.it: Lotta all’infarto: il cuore potrà essere riparato


14.04.2015 – The Jerusalem Post: Weizmann Institute researchers regenerate heart cells in mice


13.04.2015 – ScienceBlogsThe Weizmann Wave: Guest post: Dr. Gabriele D’Uva: How to Grow New Heart Cells


13.04.2015 – Il Resto del Carlino: Nuove cellule grazie alla ricerca. Così si ripara il cuore infartuato


13.04.2015 – Popular Science: Scoperta la chiave per riparare il cuore infartuato


13.04.2015 – Science Daily: Heart cells regenerated in mice


13.04.2015 – HealthCanal: Heart Cells Regenerated in Mice


13.04.2015 – Il Sole 24 Ore: Cuore, identificato gene capace di “ripararlo”


12.04.2015 – Il Quotidiano di Puglia: Con questo gene riparerò il cuore


09.04.2015 – The Australian: Bashing corporate Australia has reunited the faceless man with his Green frenemies


09.04.2015 – Medical Daily: Heart Attack Patients May Regrow Cardiac Cells By 2020 Thanks To Breakthrough Discovery


08.04.2015 – The Times of Israel: Medical leap as Israeli researchers regrow heart cells


07.04.2015 – SKY NEWSBreakthrough Sees Heart Muscle Cells Regrown


06.04.2015 – The Sydney Morning Herald: Australian researchers help find way to regrow heart muscle


06.04.2015 – The Guardian: Heart muscle cells regrown in medical research breakthrough


01.03.2015 – Popular Science: Israele, dove la tecnologia è realtà


24.10.2014 – Huffington PostDoes Cancer Grow More Aggressively at Night?


16.10.2014 – EACR (European Association for Cancer Research)TUMOURS MIGHT GROW FASTER AT NIGHT


10.10.2014 – Jerusalem PostTumors may grow faster at night, say Weizmann scientists


09.10.2014 – TIMEWhy Cancer Drugs May Work Better While You Sleep


08.10.2014 – HaaretzNight time may be the right time to treat cancer, find Israeli scientists


08.10.2014 – The Times of IsraelTumors may grow faster at night, Israeli study shows


07.10.2014 – Daily MailCancerous tumours ‘grow faster at night’ – and drugs to fight the disease might work better during sleep, study finds

06.10.2014 – Forbes:  Cancer May Grow Faster While We Sleep


01.01.2013 – Salusan: Le eccellenze salentine: Gabriele D’Uva

TV AND RADIO NEWS

23.04.2015 – RAI3TGR Emilia Romagna (min. 15:34)


15.04.2015 – Sanità Salento: Un cuore rigenerato per gli infartuati


13.04.2014 –RAI3TG Mediterraneo (min 8:32)


10.10.2013 – RAI3TG Leonardo (min 0:54)


08.04.2015 – SBS World NewsResearchers Trigger Heart Regeneration After Heart Attack

Awards and honours

2017: ERA-CVD 2016 grant award for “Transnational Research Projects on Cardiovascular Diseases” of European Union’s Horizon 2020 Framework Programme; Role: Principal Investigator (research partner) in collaboration with Hubrecht Institute (Netherlands), Ulm University (Germany) and Weizmann Institute of Science (Israel).


2008-2017: Invited or selected as speaker in international and national conferences


July 21-25, 2016: Travel grant funded by ABCD (Association of Cell Biology and Differentiation) for the participation to the “12th International Congress of Cell Biology – ICCB 2016” (Prague, Czech Republic)


November, 2015: Invited commentary article: D’Uva G and Lauriola M, Shaping ERBB Signalling by Steroid Hormones, Journal of Steroids & Hormonal Science, 2016.


May, 2015: Our publication “ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation” (D’Uva et al., Nature Cell Biology, 2015) has been cited by the National Association for Biomedical Research as an example of successful biomedical research that justifies the essential need for animals in medical research (NABR: The Essential Need for Animals in Medical Research)


April-May, 2015: Our publication “ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation” (D’Uva et al., Nature Cell Biology, 2015) has been commented/highlighted in prestigious scientific journals:
• Nature – News and Views: Regenerative biology: Neuregulin 1 makes heart muscle
• Science – News: New hope for heart attack sufferers?
• Nature Reviews Drug Discovery: Research Highlights


May, 2015: Invited review article: D’Uva G and Lauriola M, Towards the emerging cross-talk: ERBB family and steroid hormones, Seminars in Cell and Developmental Biology, 2016


May, 2015: Invited editorial article: D’Uva G and Tzahor E, The key roles of ERBB2 in cardiac regeneration, Cell Cycle 2015.


April-May, 2015: International media coverage (including The Guardian, The Sydney Morning Herald, SKY NEWS, The Times of Israel, Il Sole 24 Ore and La Repubblica) for our publication “ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation” (D’Uva et al., Nature Cell Biology, 2015).


October-November 2014: International media coverage (including TIME, Daily Mail and Huffington Post) for the collaborative publication “Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment” (Nature Communications, 2014).


December 2, 2012: Winner (first place) of the poster session of “4th Young Investigator Stem Cell Meeting” (Tel Aviv, Israel) organized by Israeli Stem Cells Society (ISCS)


May, 2011: The collaborative publication “CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions” (Nature Immunology, 2011) obtained:
• the cover of Nature Immunology (May 2011)
• a commentary article in Nature Immunology (May 2011)


2010 – Sergio Lombroso fellowship for cancer research, Israel


2010 – “Marco Polo” fellowship for abroad research activity, University of Bologna, Italy


2008 – Fellowship at “Experimental Pathology Department” of Bologna University, Italy