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3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target
  1. Antonello Villa1,
  2. Daniela Belloni2,
  3. Barbara Vergani1,
  4. Simone Cenci3,
  5. Giulio Cavalli4,5,
  6. Riccardo Biavasco5,6,
  7. Monica Rodolfo7,
  8. Maria Giulia Cangi8,
  9. Claudio Doglioni5,8,
  10. Lorenzo Dagna4,5,
  11. Elisabetta Ferrero2,
  12. Marina Ferrarini2
  1. 1 Consorzio MIA, University of Milano-Bicocca, Milan, Italy
  2. 2 Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
  3. 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
  4. 4 Unit of Immunology, Rheumatology, Allergy and Rare Diseases, San Raffaele Scientific Institute, Milan, Italy
  5. 5 Vita-Salute University, Milan, Italy
  6. 6 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute, Milan, Italy
  7. 7 Department of Experimental Oncology and Molecular Medicine, IRCCS, Istituto Nazionale per Cura dei Tumori, Milan, Italy
  8. 8 Pathology Unit, San Raffaele Scientific Institute, Milan, Italy
  1. Correspondence to Marina Ferrarini, Division of Experimental Oncology, San Raffaele Scientific Institute, Milan 20132, Italy; ferrarini.marina{at}

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Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterised by tissue infiltration by foamy CD68+ CD1a histiocytes.1 The disease has pleomorphic clinical manifestations, including long bones and extraskeletal involvement, and may be life-threatening, particularly when heart and central nervous system are affected.1

ECD histiocytes secrete proinflammatory cytokines2 and carry activating mutations along the RAS-RAF-MEK-ERK protein kinase signalling pathway, most commonly the BRAFV600E oncogenic mutation.3 4 Accordingly, patients with ECD have been treated with cytokine inhibitors, including infliximab, 5 and, more recently, with the BRAFV600E inhibitor vemurafenib.6 The latter, however, induces sustained but partial clinical responses and recurrences on discontinuation,6 underlining the need for more effective therapeutic strategies.

To identify the outcomes downstream constitutive ERK phosphorylation in ECD histiocytes and their response to small molecule-based inhibition, we performed three-dimensional (3D) culture of tissues from three BRAFV600E-mutated ECD patients in the RCCS bioreactor7 (and online supplementary methods) in the presence/absence of vemurafenib or infliximab, used as control.

Supplementary data


All patient samples maintained production of prototypical cytokines and chemokines2 in bioreactor, thus validating this technology also for ECD; moreover, infliximab, and, to a lesser degree, vemurafenib, significantly decreased cyto-chemokines and …

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