Abstract 5097
Background
Sarcoma are a heterogeneous group of tumor which can be split into two subgroups with distinct genetics. Half of sarcoma presents an important genomic reorganization correlated to tumor aggressiveness. At this stage, the origin of this instability is still unknown. Cell fusion is a physiological mechanism involved in several processes including myoblast differentiation and already described to be involved in aneuploidy generation and genomic instability. We thus hypothesized that cell fusion could participate to sarcoma oncogenesis by generating genomic instability.
Methods
We established cell line of hybrids from spontaneous fusion of immortalized myoblasts. Tumor and metastasis development were evaluated upon grafting and whole genome and transcriptome sequencing with in-vitro mechanistic studies were performed to decipher phenotypes acquired by hybrids upon fusion.
Results
In vitro hybrid cell lines show a more aggressive phenotype than parental cell lines by increasing proliferation and clonogenic capacities. Only hybrids form tumors upon grafting and may develop also metastasis. Aneuploidy triggered by cell fusion induces genome reorganization and in vivo tumor genome show alterations corresponding to those observed in human rhabdomyosarcoma. Indeed, 85% of hybrid tumors harbor DMD deletions as observed in sarcoma with myogenic origin. The study of this protein reveals that tumors lose the expression of Dp427 isoform which is the one reported as a tumor suppressor. This malignant transformation of hybrids is associated to transcriptomic remodeling toward a decrease of the expression of genes involved in muscle differentiation.
Conclusions
To our knowledge, this is the first model able to reproduce the complex genomic of sarcoma. The detection of those hybrid cells in sarcoma tumor allowed us to push forward they are involved in sarcoma development and progression and their quantification in tumors or in circulating cells could thus establish an early prognostic marker. Finally, specific therapeutic targeting of this hybrids could represent new approach.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Frederic Chibon.
Funding
Association pour la Recherche contre le Cancer (ARC) Fondation pour la Recherche Médicale (FRM).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract
2185 - Sequential treatment with afatinib followed by 3rd generation EGFR-TKI – subgroup analysis of the GIDEON trial: a prospective non-interventional study (NIS) in EGFR mutated NSCLC patients in Germany
Presenter: Wolfgang Brückl
Session: Poster Display session 1
Resources:
Abstract
1524 - Effectiveness of sequencing TKIs in patients with EGFR mutation-positive Non-small-Cell Lung Cancer (NSCLC): A French National medico administrative claim database analysis
Presenter: Nicolas Girard
Session: Poster Display session 1
Resources:
Abstract
5733 - Phase II study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation: A multicenter trial of the Korean Cancer Study Group (LU17-19)
Presenter: Tae Min Kim
Session: Poster Display session 1
Resources:
Abstract
5440 - Different stories for different EGFR exon 19 deletion variants
Presenter: Chao Zhao
Session: Poster Display session 1
Resources:
Abstract
2982 - Safety and activity of alflutinib in patients with advanced EGFR T790M mutation non-small cell lung cancer who progressed after EGFR-TKI therapy
Presenter: Yuan-Kai Shi
Session: Poster Display session 1
Resources:
Abstract
4002 - Afatinib followed by osimertinib in patients with EGFR mutation-positive (EGFRm+) advanced NSCLC: updated data from the GioTag real-world study
Presenter: Maximilian Hochmair
Session: Poster Display session 1
Resources:
Abstract
2941 - Treatment patterns of EGFR mt+ NSCLC IV pts: Real world data of the NOWEL network
Presenter: Julia Roeper
Session: Poster Display session 1
Resources:
Abstract
4154 - TP53 mutations predicts worse prognosis in EGFR-mutated NSCLC patients receiving TKIs in first- or further line of treatment
Presenter: Matteo Canale
Session: Poster Display session 1
Resources:
Abstract
1175 - HER3 ligand heregulin expression and clinical implication in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors
Presenter: Kimio Yonesaka
Session: Poster Display session 1
Resources:
Abstract