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Simone Cenci, MD - “Autophagy in plasma cell pathophysiology”

Head, Age Related Diseases, San Raffaele Scientific Institute, & Università Vita-Salute San Raffaele, Milan, Italy
When Dec 13, 2016
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Autophagy in Plasma Cell Pathophysiology
Simone Cenci, MD
San Raffaele Scientific institute, Milano
Aging progressively impairs immune functions, including serological memory, a unique property of adaptive immunity afforded by bone marrow (BM) long-lived plasma cells (PCs) residing in dedicated, poorly understood niches. Aging reduces BM PCs and predisposes them to transform in the incurable cancer multiple myeloma (MM). The intrinsic and environmental mechanisms that maintain a healthy PC niche and how aging compromises them are elusive. Autophagy, a key proteostatic asset, opposes senescence, but is weakened by aging. Following our discovery that autophagy is essential to maintain BM PCs, we devoted efforts to investigate the underlying mechanisms and its role in MM. Our work reveals an unanticipated control linking autophagy to PC differentiation; discloses new levels of integration between protein homeostasis and other cellular functions; and identifies putative BM environmental circuits co-opted by MM development.

 

Simone Cenci, M.D. is Head of the Unit of Age Related Diseases at the San Raffaele Scientific Institute, Milano, Italy. After his M.D. degree in Perugia (1995), Dr. Cenci received his post-doctoral research training in the Division of Bone and Mineral Diseases, Department of Internal Medicine at Washington University in St. Louis, USA (1998-2003), during which he also specialized in Gerontology and Geriatrics (2000).

Dr. Cenci is a recognized expert in protein homeostasis and autophagy in plasma cell ontogenesis and malignancy (1-3). Following his seminal studies of proteasome biology and proteostasis in plasma cell differentiation (4), the Cenci lab identified the balance between proteasome workload and capacity as a causal determinant of the intrinsic sensitivity of myeloma cells to proteasome inhibitors (5,6). In search for new therapeutic strategies against myeloma, his lab explored the role and molecular mechanisms of (macro)autophagy in normal and malignant plasma cells, integrating different strategies (mouse genetics, imaging, lentiviral engineering) and devising SILAC-based unbiased proteomic techniques to disclose plasma cell-specific targets of selective autophagy (7,8). Through these approaches, the Cenci lab discovered a novel role for autophagy in plasma cell ontogenesis, critical to control antibody responses and to maintain the pool of bone marrow long-lived plasma cells, the normal counterpart of multiple myeloma (7). Moreover, his lab investigated the role and underlying mechanisms of selective autophagy in malignant plasma cells, disclosing that myeloma cells depend on the autophagic adapter, SQSTM1/p62 for viability, clonogenicity, and specific proteasome inhibitor resistance, and revealing a novel example of non-oncogene addiction (8).

Exploiting a strong background in bone biology (9-11), Dr. Cenci also investigates the complex and vicious interplay between myeloma and the bone microenvironment. To this aim, his lab recently adopted wide-scope metabolomics to assess the comprehensive bone marrow and peripheral metabolic profile of myeloma patients, defining an array of unanticipated biomarkers and putative pathomechanisms associated with myeloma progression (12).

 

  1. Milan E, Fabbri M, Cenci S. Autophagy in Plasma Cell Ontogeny and Malignancy. J Clin Immunol. 2016; 36 Suppl 1:18-24.
  2. Auner, HW & Cenci S. Recent advances and future directions in targeting the secretory apparatus in multiple myeloma. Br J Haematol. 2015; 168(1): 14-25.
  3. Pengo N & Cenci S. The role of autophagy in plasma cell ontogenesis. Autophagy 2013; 9(6): 942-4.
  4. Cenci S, Mezghrani A, Cascio P, Cerruti F, Mattioli L, Oliva L, Orsi A, Masciarelli S, Ruffato E, Pasqualetto E, Sitia R. Progressively impaired proteasomal capacity during terminal plasma cell differentiation. EMBO J 2006; 25(5): 1104-13.
  5. Bianchi G, Oliva L, Cascio P, Pengo N, Fontana F, Cerruti F, Orsi A, Pasqualetto E, Mezghrani A, Calbi V, Palladini G, Giuliani N, Anderson KC, Sitia R, and Cenci S. The proteasome load vs. capacity balance determines apoptoptic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 2009; 113: 3040-3049.
  6. Cenci S, Oliva L, Cerruti F, Milan E, Bianchi G, Raule M, Mezghrani A, Pasqualetto E, Sitia R, Cascio P. Pivotal advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J Leukoc Biol. 2012; 92(5):921-31.
  7. Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, Fagioli C, Merlini A, Mariani E, Pasqualetto E, Orfanelli U, Ponzoni M, Sitia R, Casola S, and Cenci S. Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol. 2013; 14(3): 298-305.
  8. Milan E, Perini T, Resnati M, Orfanelli U, Oliva L, Raimondi A, Cascio P, Bachi A, Marcatti M, Ciceri F, and Cenci S. A Plastic p62-Dependent Autophagic Reserve Maintains Proteostasis and Determines Proteasome Inhibitor Susceptibility in Multiple Myeloma Cells. Autophagy 2015; 11(7):1161-1178.
  9. Benasciutti E, Mariani E, Oliva L, Scolari M, Perilli E, Barras E, Milan E, Orfanelli U, Fazzalari NL, Campana L, Capobianco A, Otten L, Particelli F, Acha-Orbea H, Baruffaldi F, Faccio R, Sitia R, Reith W & Cenci SMHC Class II Transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity. J Bone Min Res. 2014; 29(2):290-303.
  10. Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qien WP, Sierra O, Pacifici R. Estrogen deficiency causes bone loss by upregulating T cell proliferation and lifespan through IFNγ induced class II transactivator. Proc Natl Acad Sci USA 2003; 100(18): 10405-10.
  11. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Pacifici R. Estrogen deficiency induces bone loss by enhancing T cell production of TNFα. J Clin Invest. 2000; 106(10):1229-37.
  12. Cenci S, Fontana F, Garcia Manteiga JM. “BIOMARKERS OF MULTIPLE MYELOMA DEVELOPMENT AND PROGRESSION”. International patent WO2014/068144. 

Emilio Hirsch, Ph.D. - "3-phosphorylated Phosphoinositides in primary cilium and mitosis"

Professor of Experimental Biology Department of Molecular Biotechnology and Health Sciences Center for Molecular Biotechnology Via Nizza 52 10126 Torino - Italy
When Dec 20, 2016
from 12:00 PM to 01:35 PM
Where Tigem Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Achille Iolascon, MD, PhD - CEINGE Biotecnologie Avanzate and Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II di Napoli, Italy

When Jan 24, 2017
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Tiziano Bandiera, Ph.D. - Italian Institute of Technology Drug Discovery and Development Unit, Genova, Italy

When Feb 07, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Tiziano Bandiera studied at the University of Pavia (Italy) where he earned his Ph.D. degree in Chemistry in 1987.

He moved then to the pharmaceutical industry and worked at Farmitalia-Carlo Erba, Pharmacia Corp., and Nerviano Medical Sciences. His career in the industry started as researcher in the Central Nervous System therapeutic area, where his main activity was targeted at the discovery of potential new treatments for Alzheimer’s disease. In 1998, he moved to the Oncology field, and worked as project leader of preclinical discovery projects focusing on the search for antagonists of the αvß3 integrin, tyrosine kinase inhibitors, and inhibitors of arginine methyltransferases.

In 2008, he joined the Istituto Italiano di Tecnologia to set up the Medicinal Chemistry group of the Drug Discovery and Development (D3) department. Since 2013, he is the head of the PharmaChemistry Facility of the D3 department.  His research activities are focused on the identification of potential new drugs for the treatment of cystic fibrosis, pain, and inflammatory diseases.

Dr. Bandiera has published more than 50 papers in peer-reviewed journals and is an inventor in 36 patents and patent applications. He is member of the Board of the Medicinal Chemistry Division of the Italian Chemical Society.