BIO

Dr. Enrico Milan obtained his master’s degree in Medical Biotechnology at Università Vita-Salute San Raffaele, specializing himself in proteomics (Milan et al., 2012). In 2014, he received his PhD in Molecular Medicine at Università Vita- Salute San Raffaele investigating the role of autophagy in normal and malignant plasma cells in the lab of Prof. Simone Cenci (Pengo et al., 2013; 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 analysis of its interactors. In 2015, he was visiting postdoctoral fellow in Prof. Jorge Moscat Lab at Sanford Burnham Prebys Medical Discovery Center, La Jolla CA, USA. He was awarded by national and international funding agencies with the Multiple Myeloma Research Foundation (MMRF) Research Award 2016, the International Myeloma Foundation (IMF) Research grant (2019) and the Fondazione Cariplo Giovani Ricercatori 2018. As principal investigator, he characterized the biological role of multiple myeloma tumor suppressor FAM46C/TENT5C in regulating antibody secretion and myeloma growth (Fucci et al., 2020, Perini et al., 2022, Resnati et al., 2024). This opened new lines of research focused on investigating novel molecular pathways modulating multiple myeloma proteostasis, antibody production and drug sensitivity. His research activity is supported by Fondazione Telethon and Cariplo (Joint Grant on Rare Diseases) and Ministero della Sanità (Ricerca Giovani Ricercatori 2018 and 2019).

Lab

Brief Introduction

Multiple myeloma is a still incurable tumor of plasma cells responsible for 2% of all cancer deaths. Plasma cells are highly specialized secretory factories, derived from B lymphocyte differentiation, professionally devoted to antibody production and secretion. This massive effort causes a dependency of myeloma cells on pathways ensuring equilibrium between immunoglobulin synthesis, folding, secretion and degradation, as witnessed by the extraordinary success of proteasome inhibitors in the clinic. Strengthening the relevance of this delicate coordination, mutations in genes driving plasma cell differentiation have been identified in multiple myeloma patients (Perini et al., 2022).

RESEARCH ACTIVITY

Our research activity is focused on the dissection of the molecular mechanisms regulating protein homeostasis and secretion in normal and malignant plasma cells. In particular, we have recently contributed to discover that the myeloma tumor suppressor FAM46C/TENT5C, which is lost in up of 20% of patients, is a non-canonical poly(A)polymerase that rapidly and potently promotes antibody secretion (Fucci et al., 2020, Resnati et al., 2024). Our discoveries reveal a selective pressure in multiple myeloma to reduce the cellular stress associated with immunoglobulin production to favor tumor growth. Ongoing projects in the lab are investigating the FAM46C-associated molecular circuits modulating immunoglobulin synthesis and trafficking along the secretory route and are characterizing the role of mutations in plasma cell identity factors in myeloma pathobiology to unveil new vulnerabilities to be exploited against this frequent and still incurable malignancy.

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