Stefano Bestetti

Multiple myeloma (MM) is a malignant disease characterized by the accumulation of clonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin (Ig) in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency.

The first stage in the development of MM is the appearance of an asymptomatic monoclonal gammopathy of undetermined significance (MGUS). In some of these patients, this MGUS progresses to smoldering myeloma and ultimately to symptomatic MM.

Progression to MM stage is associated with a series of genetic events in neoplastic cells, as well as changes in the bone marrow microenvironment. These changes usually correlate with the clinical features of MM and its resistance to treatments.

Recent metabolomic studies have unveiled the importance of some metabolic pathways potentially involved in redox homeostasis in the neoplastic evolution of MM cells, especially in the crosstalk with the tumor site (stromal cells in the bone marrow).

Having developed a panel of ratiometric H2O2 sensors (HyPer Vectors) targeted into different organelles, to analyse H2O2 fluxes into and inside living cells, in the lab we have shown before that H2O2 transport across the plasma membrane requires aquaporin 8 (AQP8) and possibly other protein channels. We have also observed that certain cellular stress conditions reversibly inhibit AQP8-mediated H2O2 entry into cells, impacting signaling. As in this kind of tumor, an early diagnosis is really important in order to efficiently improve the patients’ response to treatments, it is clear that the study and monitoring with HyPer of the redox-related pathways active in a normal plasma cell population compared to MM, could be essential to reveal new strategies to treat the disease.

Publications:

A persulfidation-based mechanism controls Aquaporin-8 conductance.

Bestetti S*, Medraño-Fernandez I*, Galli M, Ghitti M, Bienert GP, Musco G, Orsi A, Rubartelli A, Sitia R.

Sci Adv. 2018 May 2;4(5):eaar5770. doi: 10.1126/sciadv.aar5770. eCollection 2018 May.

Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival.

Medraño-Fernandez I*, Bestetti S*, Bertolotti M, Bienert GP, Bottino C, Laforenza U, Rubartelli A, Sitia R.

Antioxid Redox Signal. 2016 Jun 20;24(18):1031-44. doi: 10.1089/ars.2016.6636. Epub 2016 Apr 19.

Response to Marinelli and Marchissio.

Bertolotti M, Bestetti S, Medrano-Fernandez I, Sitia R.

Antioxid Redox Signal. 2013 Sep 10;19(8):897. doi: 10.1089/ars.2013.5505rs. No abstract available.

Tyrosine kinase signal modulation: a matter of H2O2 membrane permeability?

Bertolotti M*, Bestetti S*, García-Manteiga JM*, Medraño-Fernandez I*, Dal Mas A, Malosio ML, Sitia R.

Antioxid Redox Signal. 2013 Nov 1;19(13):1447-51. doi: 10.1089/ars.2013.5330. Epub 2013 Sep 18.