Enrico Milan RicercatoreMedicine
Plasma cells are the terminal effectors of B cell differentiation responsible for antibody secretion. Immunoglobulin production causes a critical dependence of these cells in the two principal protein degradative pathways: the ubiquitin-proteasome system and autophagy. The most relevant implication of this addiction is the extraordinary efficacy of proteasome inhibitors in the treatment of plasma cell dyscrasias (i.e. multiple myeloma and systemic light chain amyloidosis). However, not all the patients respond to proteasome inhibitors or resistance ensues. Understanding the cellular mechanisms ensuring protein homeostasis in plasma cells may unveil new therapeutic targets to increase proteasome inhibitor efficacy and overcome resistance.
Our research is focused on the study on how plasma cells regulate the secretory capacity, in efficient coordination with protein degradative pathways to discover new therapeutic targets against multiple myeloma and systemic light chain amyloidosis.
In particular, we are interested in autophagy, a cellular catabolic pathway that engulfs through specific receptors intracellular substrates in double-membrane vesicles (autophagosomes) subsequently delivered to the lysosome for content degradation and recycling. Notably, we discovered that autophagy is essential for myeloma survival and that the receptor SQSTM1/p62 is a critical mediator of the autophagic clearance of ubiquitinated proteins and affords specific protection against proteasome inhibitors (Milan et al., 2015). Dissecting the degradative targets of p62 in plasma cells, we identified novel interactors potentially involved in maintaining the delicate equilibrium between the secretory capacity and protein homeostasis. The investigation of these new molecular circuits may be translated into new therapeutic strategies in order to decrease pathogenic plasma cell viability and improve proteasome inhibitor efficacy.
Enrico obtained his master degree in Biotechnology at Università Vita-Salute San Raffaele, after an internship in the Biomolecular Mass Spectrometry Lab directed by Dr. Angela Bachi in 2009. During this experience he specialized himself in proteomics and he identified serum biomarkers able to predict patient response to EGFR inhibitor in non-small cell lung cancer (Milan et al., 2012).
In 2014, he received a PhD in Molecular Medicine at Università Vita- Salute San Raffaele in the lab of Dr. Simone Cenci investigating the role of autophagy in multiple myeloma (Milan et al. 2015). During these years he characterized the functions of the autophagic receptor of ubiquitinated proteins p62/SQSTM1 in multiple myeloma through an extensive and unbiased proteomic analyses of its interactors.
This opened a new line of research focused on investigating how novel p62-dependent molecular circuits impact on plasma cell proteostasis and drug sensitivity.
His research activity is supported by International Myeloma Foundation (IMF Brian D. Novis Research Grant), Fondazione Cariplo (Ricerca Biomedica Condotta da Giovani Ricercatori) e Ministero della Sanità (Ricerca Giovani Ricercatori 2018). Enrico has published 12 articles in peer-reviewed journals. His work has been cited > 1300 times, with an H-index of 8 (Scopus source).
Total Publications: 12 h-index: 8 (Scopus Author ID: 55314279400; ORCID: 0000-0003-3094-4275)
- Battista RA, Resnati M, Facchi C, Ruggieri E, Cremasco F, Paradiso F, Orfanelli U, Giordano L, Bussi M, Cenci S, Milan E. Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation. PLOS ONE. 2018 Aug 1;13(8):e0201621. doi: 10.1371/journal.pone.0201621.
- Milan E, Perini T, Resnati M, Orfanelli U, Oliva L, Raimondi A, Cascio P, Bachi A, Marcatti M, Ciceri F & Cenci S. A Plastic p62-Dependent Autophagic Reserve Maintains Proteostasis and Determines Proteasome Inhibitor Susceptibility in Multiple Myeloma Cells. Autophagy 2015;11(7):1161-78.
- Milan E, Fabbri M, Cenci S. Autophagy in Plasma Cell Ontogeny and Malignancy. J Clin Immunol. 2016 May; 36 Suppl 1:18-24. doi: 10.1007/s10875-016-0254-9. Epub 2016 Mar 16.
- Milan E, Lazzari C, Anand S, Floriani I, Torri V, Sorlini C, Gregorc V, Bachi A. SAA1 is over-expressed in plasma of non small cell lung cancer patients with poor outcome after treatment with epidermal growth factor receptor tyrosine-kinase inhibitors. J Proteomics. 2012; 76 Spec No.:91-101.
- 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, 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.
- Klionsky DJ, (…), Milan E, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016, Jan 2;12(1):1-222.
- Zhang XD, Baladandayuthapani V, Lin H, Mulligan G, Li B, Esseltine DL, Qi L, Xu J, Hunziker W, Barlogie B, Usmani SZ, Zhang Q, Crowley J, Hoering A, Shah JJ, Weber DM, Manasanch EE, Thomas SK, Li BZ, Wang HH, Zhang J, Kuiatse I, Tang JL, Wang H, He J, Yang J, Milan E, Cenci S, Ma WC, Wang ZQ, Davis RE, Yang L, Orlowski RZ. Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling. Cancer Cell. 2016 May 9;29(5):639-52. doi: 10.1016/j.ccell.2016.03.026. Epub 2016 Apr 28.
- Maroni P, Bendinelli P, Resnati M, Matteucci E, Milan E, Desiderio MA. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages. Int J Mol Sci. 2016 Mar 25;17(4).
- 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 Feb;29(2):290-303
- 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
- Auner HW, Moody AM, Ward TH, Kraus M, Milan E, May P, Chaidos A, Driessen C, Cenci S, Dazzi F, Rahemtulla A, Apperley JF, Karadimitris A, Dillon N. Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells. PLoS One. 2013, 8(9): e74415. doi:10.1371
- 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
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