Identification of a gene expression driven progression pathway in myxoid liposarcoma

// Loris De Cecco 1,* , Tiziana Negri 2,* , Silvia Brich 2 , Valentina Mauro 2 , Fabio Bozzi 2 , GianPaolo Dagrada 2 , Vittoria Disciglio 1 , Roberta Sanfilippo 3 , Alessandro Gronchi 4 , Maurizio D’Incalci 5 , Paolo G. Casali 3 , Silvana Canevari 1 , Marco A. Pierotti 6 and Silvana Pilotti 2 1 Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Italy 3 Adult Mesenchymal Tumor Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 4 Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Department of Oncology, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 6 Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy * These authors contributed equally to this work Correspondence: Silvana Pilotti, email: // Tiziana Negri, email: // Keywords : myxoid liposarcoma; progression to round cell; gene expression array; epigenetic deregulation; stemness related genes; fast cell cycle related genes Received : April 25, 2014 Accepted: May 25, 2014 Published: May 27, 2014 Abstract Aim: to investigate the events involved in the progression of myxoid liposarcoma (MLS). Gene expression profiling and immunohistochemical/biochemical analyses were applied to specimens representative of the opposite ends of the MLS spectrum: pure myxoid (ML) and pure round cell (RC) liposarcomas. The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component. In this model, a switch in the vascular landscape from a normal to a pro-angiogenic signature and the silencing of DLK1-DIO3 region mark the progression from ML to RC in concert with the acquisition by the latter of the over-expression of YY1/C-MYC/HDAC2, together with over-expression of genes involved in cell proliferation and stemness: MKNK2 , MSX1 and TRIM71 . Taken together, these findings strongly suggest that to progress from ML to RC liposarcoma the cells have to overcome the epigenetic silencing restriction point in order to reset their new stem-like differentiation signature. Our findings provide a first attempt at identifying the missing links between ML and RC liposarcomas, that may also have broader applications in other clinico-pathological settings characterised by a spectrum of progression.