Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Alessandro Morotti - PI
Associate Professor - Department of Clinical and Biological Sciences
Giovanna Carrà PhD postdoctoral fellow
Maria Vittoria Manno student
Arianna Nebbia Colomba student
Sofa Camerlo MD
Giorgio Rosati MD
RESEARCH EXPERIENCES
I started my first research experiences in 1998 with the supervision of Prof. Carola Ponzetto; next I Joined the Hematological Division directed by Prof. Giuseppe Saglio at the AUO San Luigi - Orbassano, where I mostly studied signaling pathways in myeloproliferative neoplasms. After my residency, I worked as a research fellow in Prof. Pier Paolo Pandolf laboratory at the Memorial Sloan Kettering Cancer center in New York and then at the BIDMC of Boston. Clinical experiences: I develop my clinical expertise at that the Division of Hematology of San Luigi Hospital, under the supervision of Prof. Giuseppe Saglio. I am currently working as associate Professor at the same division, where I am mostly focusing on cancer associated thrombosis and hematological malignancies.
Background
Cancer Associated Thrombosis (CAT) is the second most frequent cause of death in patients with cancer, second only to disease progression. Conversely, cancer is the most frequent cause of death in patients with venous thromboembolism. Cancer and thrombosis are indeed intimately connected. Beside individual risk factors, CAT incidence varies based on tumor type, with cancers of the pancreas, lung, stomach and lymphomas at the highest risk of thrombosis. Various mechanisms have been associated with increased risk of thrombosis, including the expression of procoagulant factors from the tumor and the recruitment of inflammatory cells by the tumor itself. However, a more general and targetable mechanisms is still missing. Cancer is also the most frequent cause of death in patients with venous thromboembolism, therefore it is tempting assuming that thrombosis could favor cancer progression as well. Overall, deciphering the crosstalk between coagulation pathways and cancer is of essential clinical importance, with potentially relevant implications in thrombosis prevention and inhibition of cancer progression.
Research aims
Our lab aims to address the link between aberrantly activated signal transduction pathways and the hemostatic process in cancers of different origin. We intend to determine: → how cancer affects microenvironment including endothelial cells and immune system recruitment. → how cancer, in particular lung cancer and myeloproliferative neoplasms, triggers clot system and platelets, therefore leading to thrombosis.
Previous discoveries
We start our investigations to assess the contribution of various pathways in the development of both myeloproliferative neoplasms and lung cancers. We were interested in both types of cancers due to the observation that similar pathways were able to develop both myeloproliferative neoplasia and lung cancer (as we published in Nat Genet. 2010 Mar;42(3):216-23.). We spent most of our energies in the assessment of the role of NFkB/IkBalpha in such cancer models. Very recently, we demonstrated that this pair is playing an essential role in the modulation of cancer cell metabolism, with potentially relevant implications in the modification of the tumoral microenvironment, involving endothelial cell activation and immune system recruitment. Parallel to these investigations, we were also interested in the determination of how aberrant pathways can lead to thrombosis. In particular, we recently demonstrated that various gene mutations (DNMT3A and TET2 point mutations) are associated with increased thrombosis manifestations in a particular group of patients. We are therefore trying to link aberrant pathways to thrombosis development.
Current research is focusing to assess whether aberrant activation of NF-KB/IkB-alpha is able to affect tumor microenvironment, favoring the activation of the endothelial cells of tumoral vessels. Activated endothelial cells are indeed able to promote both neo-angiogenesis and favoring cancer associated thrombosis. Such investigations are designed to identify mechanisms of CAT development and to define new therapeutic strategies to prevent thrombosis. Finally, the contribution of thrombosis, as a potential source of growth factor derived from the clots, in tumorigenesis are also investigated.
Ricerca finalizzata dal Ministero della salute to Alessandro Morotti: "Definition of the role of IkB-alpha in the pathogenesis and progression of Chronic Myeloid Leukemia”. 304.109 euros
Ricerca finalizzata Ministero della salute to Giovanna Carrà: “GR-20212374957 denominato “NF-kB positively regulates Fatty Acid Oxidation in cancer cells, which hinders CD8+ T lymphocytes and promotes tumor progression.
Carrà G, Giugliano E, Camerlo S, Rosati G, Branca E, Maffeo B, Russo I, Piazza R, Cilloni D, Morotti A. Clonal hematopoiesis by DNMT3A mutations as a common finding in idiopathic splanchnic vein thrombosis. Haematologica. 2023 May 1;108(5):1447-1449
Carrà G, Ermondi G, Riganti C, Righi L, Caron G, Menga A, Capelletto E, Maffeo B, Lingua MF, Fusella F, Volante M, Taulli R, Guerrasio A, Novello S, Brancaccio M, Piazza R, Morotti A. “IκBα targeting promotes oxidative stress-dependent cell death”. J Exp Clin Cancer Res. 2021 Apr 16;40(1):136.
Barale C, Senkeev R, Napoli F, De Gobbi M, Guerrasio A,Morotti A, Russo I. “Transferrin saturation inversely correlates with platelet function”. Thromb Haemost. 2019 May;119(5):766- 778
Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A, Brancaccio M. (CO-LAST AUTHOR) “Morgana acts as an oncosuppressor in chronic myeloid leukemia”. Blood. 2015 Apr2;125(14):2245-53.
Morotti A, Panuzzo C, Crivellaro S, Pergolizzi B, Familiari U, Berger AH, Saglio G, Pandolfi PP. “BCR-ABL disrupts PTEN nuclear cytoplasmic shuttling through phosphorylation dependent activation of HAUSP”. Leukemia. 2014 Jun;28(6):1326-33.
Berger AH, Niki M, Morotti A, Taylor BS, Socci ND, Viale A, Brennan C, Szoke J, Motoi N, Rothman PB, Teruya-Feldstein J, Gerald WL, Ladanyi M, and Pier Paolo Pandolfi. “Identification of DOK family genes as lung tumor suppressors”. Nature Genetics. 2010 Mar;42(3):216-23.
Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J and Pandolfi PP. “PML targeting eradicates quiescent leukaemia-initiating cells”. Nature. 2008 Jun 19;453(7198):1072-8.
Morotti A, Parvis G, Cilloni D, Familiari U, Pautasso M, Bosa M, Messa F, Arruga F, Defilippi, Catalano R, Rosso V, Carturan S, Bracco E, Guerrasio A and Saglio G. “CD7/CD56 positive Acute Myeloid Leukemias are characterized by constitutive phosphorylation of the NF-kB subunit p65 at Ser 536". Leukemia. 2007 Jun;21(6):1305-6.
Morotti A, Cilloni D, Messa F, Arruga F, Defilippi I, Carturan S, Catalano R, Rosso V, Chiarenza A, Pilatrino C, Guerrasio A, Taulli R, Bracco E, Pautasso M, Baraban D, Gottardi E and Saglio G. “Valproate enhances Imatinib-induced growth arrest and apoptosis in Chronic Myeloid Leukemia Cells”. Cancer.2006;106:1188-1196.
Morotti A, Mila S, Ponzetto C: “K252a inhibits the oncogenic properties of Met, the HGF receptor”. Oncogene, 2002 (21): 4885-4893.
Scopus ID Alessandro Morotti: 6507221286
