Age related diseases
Research is focused on the biology of plasma cells (PC), terminally differentiated effectors of antibody responses, and their malignant counterpart, multiple myeloma (MM), and integrates hypothesis-driven and agnostic, wide- scope approaches (proteomics and metabolomics).
The Unit is particularly interested in autophagy, a crucial asset ensuring proteome plasticity, across PC ontogenesis, in immunity, i.e., in the control of antibody responses and in the maintenance of serological memory, and in the pathobiology of MM.
Troubled protein homeostasis is an established stress phenotype of cancer that provides unexpected therapeutic specificity, with MM as the paradigm of proteasome inhibitor (PI) responsive cancers. After contributing to clarify the bases of the unique sensitivity of MM to PIs, the research group disclosed a novel, specific and essential function of autophagy in PC ontogenesis, required for the maintenance of the bone marrow memory PC niche, the normal counterpart of MM.
Next, the unit defined the protein and organelle-homeostatic functions of autophagy in MM, and identified a novel non-oncogene addiction of this malignancy to the prototypical autophagy adapter SQSTM1/p62 and unique organellar stress features in neoplastic PCs.
These discoveries provide a powerful framework for identifying new molecular targets against PC malignancies. Synergic studies on the skeletal microenvironment help explore the vicious relationship of MM with the bone marrow.
Oliva L, Orfanelli U, Resnati M, Raimondi A, Orsi A, Milan E, Palladini G, Milani P, Cerruti F, Cascio P, Casarini S, Rognoni P, Touvier T, Marcatti M, Ciceri F, Mangiacavalli S, Corso A, Merlini G and Cenci S. The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity. Blood 2017 Apr 13;129(15):2132-2142.
Milan E, Fabbri M, Cenci S. Autophagy in plasma cell ontogeny and malignancy. J Clin Immunol. 2016; 36 Suppl 1:18-24.
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.
Auner, HW and Cenci S. Recent advances and future directions in targeting the secretory apparatus in multiple myeloma. Br J Haematol. 2015;168(1):14-25.
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 and Cenci S. MHC 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.
Pengo N and Cenci S. The role of autophagy in plasma cell ontogenesis. Autophagy. 2013; 9(6):942-4.
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.
Cenci S. The proteasome in terminal plasma cell differentiation. Semin Hematol. 2012; 49(3):215–222.
Cenci S, van Anken E, Sitia R. Proteostenosis and plasma cell pathophysiology. Curr Opin Cell Biol. 2011; 23(2):216-22.
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.