The laboratory works in close collaboration with the Pediatric Hematology Oncology Division in Padua. Over the years, it has developed a particular interest in diagnostics, basic and translational research for children with soft tissue sarcomas and other rare tumors.
The main activities are:
i) collect, handle and store biological samples from patients with solid tumors: a pediatric soft tissue biobank was established since 1995 and every year the laboratory analyzes almost 150 new cases collected from more than 30 pediatric oncology centers part of the AssociazioneItaliana di Ematologia e OncologiaPediatrica (AIEOP), performing more than 1000 molecular analyses with diagnostic and prognostic significance.
ii) provide the necessary molecular biology investigations to support the diagnosis of sarcoma: the laboratory is involved in the investigation of new diagnostic and prognostic biomarkers in children with soft tissue sarcomas (STS). In many of these malignancies we have demonstrated the presence of several new genetic abnormalities, including point mutations, deletions, amplifications and chromosomal translocations that have improved our ability to identify the best treatment option for each patient, both reducing the side-effects of the conventional treatments as well as identifying high risk patients suitable for novel therapeutic approaches. During these years, the number of assessed genetic alterations have progressively improved, and it now includes more than 30 specific abnormalities, like the most recentVGLL2-CITED2 and VGLL2-NCOA2 in sclerosing and spindle cell RMS (ScRMS and SRMS, respectively), TEAD1-NCOA2 or SRF-NCOA2 gene fusions in ScRMS and SRMS also, BCOR exon 16 ITD and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcomas (URCS) and primitive myxoid mesenchymal tumor of infancy (PMMTI), CIC-DUX4 and BCOR-CCNB3in a subset of pediatric undifferentiated (UND) sarcomas and translocation-negative Ewing sarcomas (ES), in addition to the more common ones routinely tested. For instance, in collaboration with the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG), we have demonstrated that the presence of fusion transcript PAX-FOXO1in the blood and bone marrow of children with alveolar rhabdomyosarcoma tumors (and lymph node involvement) has a strong impact on prognosis.
iii) promote research projects dedicated to study the biological characteristics of pediatric soft tissue sarcomas (STS) and biomarkers that can have a direct clinical application: a series of studies utilizing liquid biopsies have also been carried out by our group, in order to identify novel biomarkers predictive of cancer resistance and metastasis, throughout a comprehensive cellular and molecular analysis of peripheral blood, bone marrow and plasma samples of children with STS. Liquid biopsies are non-invasive blood tests for the detection of circulating tumor cells (CTCs), cell-free tumor DNA (ctDNA) and cancer-associated antigens shed into the bloodstream by the primary tumor and metastasis, which can help to identify tumors able to spread to distant organs and develop better strategies to predict risk of relapse. The laboratory focused on the immunoaffinity capturing and magnetic sorting set up of CTCs in children with STS (in collaboration with the Veneto Institute of Oncology, IOV), coupled to ultra-deep NGS sequencing and gene expression profiling of both CTCs and ctDNA. We also performed proteome-scale examination of STS patients’ plasma, to assess the presence of tumor antigens and matching tumor-associated autoantibodies that may help to detect the presence of tumor at diagnosis and classify patients belonging to different risk groups. By doing so, we have observed that 1) CTCs are found in the bloodstream of children with soft tissue sarcomas, 2) CTCs and cfDNA samples harbor pre-treatment tumor mutations that may be important to assess disease evolution and treatment response, 3) autoantibodies against STS tumor antigens do exist and evoke an immune response that distinguishes affected children from healthy subjects, likewise patients belonging to different risk groups. Nonetheless, a main research interest of our group remains the identification of driver genes and proteins in childhood cancer targetable by novel anticancer drug therapeutics. During the past years we have paid particular attention to small-molecule inhibitors, based on the concept that tumors carrying deregulated enzymes (i.e. tyrosine kinases) are particularly susceptible to their inhibition. We have tested several target-specific and group-selective agents, using heterogeneous and oncogene-addicted in vitro models of pediatric STS and inhibitor compounds from either research institutes or pharmaceutical companies. In collaboration with several research groups, we contributed to demonstrate 1) the potential role of ALK tyrosine kinase in tumor progression and metastasis of pediatric RMS; 2) the anti-differentiation and tumorigenic function of ZNF521 in MLL-rearranged cells; 3) the prognostic value of miR-223 in pediatric T-Cell lymphoblastic lymphoma; 4) the differential expression level of NPM-ALK fusion gene in distinct subtypes of ALCL (anaplastic large cell lymphoma) patients; 5) the preclinical activity of new tyrosine kinase inhibitors in pediatric tumors harboring ALK and TRK gene rearrangements.
Paolo Bonvini, Senior scientist
Angelica Zin, Senior post-doctoral fellows
Lucia Tombolan, Senior post-doctoral fellows
Elena Poli, Junior post-doctoral fellow
Silvia Lucchetta, PhD student
Elisa Tosato, Technician
Tombolan L, Rossi E, Zin A, Santoro L, Bonvini P, Zamarchi R, Bisogno G. Pediatric sarcomas display a variable EpCAM expression in a histology-dependent manner. Transl Oncol. 2020 Nov;13(11):100846.
Poli E, Zin A, Cattelan M, Tombolan L, Zanetti I, Scagnellato A, Bonvini P and Bisogno G. Prognostic Value of Circulating IGFBP2 and Related Autoantibodies in Children with Metastatic Rhabdomyosarcoma. Diagnostics. 2020 Feb 20;10(2).
Lopez-Nunez O, Cafferata B, Santi M, Ranganathan S, Pearce TM, Kulich SM, Bailey KM, Broniscer A, Rossi S, Zin A, Nasrallah MP, Li MM, Zhong Y, Miele E, Alaggio R, Surrey LF. The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: Experience from three pediatric institutions with review of the literature. Brain Pathol. 2020 Sep 30.
Saggioro M, D’Angelo E, Bisogno G, Agostini M, Pozzobon M. Carcinoma and Sarcoma Microenvironment at a Glance: Where We Are. Front Oncol. 2020 Mar 3;10:76.
Salgado CM, Zin A, Garrido M, Kletskaya I, DeVito R, Reyes-M√∫gica M, Bisogno G, Donofrio V, Alaggio R. Pediatric Soft Tissue Tumors With BCOR ITD Express EGFR but Not OLIG2. Pediatr Dev Pathol. 2020 Aug 13:1093526620945528.
Antonescu CR, Kao YC, Xu B, Fujisawa Y, Chung C, Fletcher CDM, Graf N, Suurmeijer AJ, Zin A, Wexler LH, Ferrari A, Bisogno G, Alaggio R. Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study. Mod Pathol. 2020 Sep;33(9):1669-1677.
Tombolan L, Zin A, Bisogno G. Cell-Free DNA in Pediatric Rhabdomyosarcoma: Potential and Challenges. Methods Mol Biol. 2019;1909:165-175.
Gallego S, Zanetti I, Orbach D, Ranch√®re D, Shipley J, Zin A, Bergeron C, de Salvo GL, Chisholm J, Ferrari A, Jenney M, Mandeville HC, Rogers T, Merks JHM, Mudry P, Glosli H, Milano GM, Ferman S, Bisogno G; European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Cancer. 2018 Aug 1;124(15):3201-3209.
Smith KM, Fagan PC, Pomari E, Germano G, Frasson C, Walsh C, Silverman I, Bonvini P, Li G. Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia. Mol Cancer Ther. 2018 Feb;17(2):455-463.
Tombolan L, Poli E, Martini P, Zin A, Romualdi C, Bisogno G, Lanfranchi G. NELL1, whose high expression correlates with negative outcomes, has differentmethylation patterns in alveolar and embryonal rhabdomyosarcoma. Oncotarget. 2017May 16;8(20):33086-33099.
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