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Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

Savary, C.; Huchede, P.; Luciana, L.; Tourbez, A.; Deligne, C.; Picard, C.; Diot, T.; Coquet, C.; Meynard, N.; Le Grand, M.; Tonon, L.; Gadot, N.; Degletagne, C.; Leon, S.; Attignon, V.; Boman, A.; Rochet, I.; Muller, K.; Mournetas, V.; Bergeron, C.; Rinaudo, P.; Dutour, A.; Cordier-Bussat, M.; Dijoud, F.; Corradini, N.; Maucort-Boulch, D.; Pasquier, E.; Blay, J.-Y.; Castets, M.; Broutier, L.

2022-09-07 cancer biology
10.1101/2022.09.06.506756 bioRxiv
Show abstract

Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS. Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of their preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data.

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