Abstract 6245: 3D-models of pediatric bone sarcomas for personalized therapeutic screening

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.6245-6245
• Main Authors: Sarikas, Branka Radic, Ilg, Mathias, Markovic, Marica, Sturtzel, Caterina, Scheuringer, Eva, Zulini, Justine, Metzelder, Martin, Halbritter, Florian, Distel, Martin, Surdez, Didier, Delattre, Olivier, Ovsianikov, Aleksandr, Kovar, Heinrich
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-6245

Osteosarcoma (OS) and Ewing sarcoma (ES) are the most common bone cancers in children. They are rare cancers and thus difficult to study due to scarcity of patient material, large genomic instability and a wide histological heterogeneity (in OS) or a lack of satisfactory transgenic animal model and availability of preclinical tests (in ES). There is a dire need for new models and novel therapeutic approaches. Although patient-derived xenografts (PDXs) may recapitulate human tumor biology and predict drug response, propagating PDXs in mice limits its use as a drug-testing platform. We have established and standardized ES and OS spheroid culture and developed a semi-automated drug-screening platform in tumor spheroids. We established several robust techniques for spheroid formation, with clear pathophysiological gradients, but without central necroses at the onset of drug treatment. We performed RNA-seq comparing spheroid transcription profiles to 2D culture and observed dramatic changes in overall expression patterns. We observed upregulation of genes shown to correlate with poor prognosis in OS patients. We saw upregulation of processes associated with regulation of cell migration, negative regulation of proliferation and modulation of the extracellular matrix (ECM). In addition to ES spheroid models, we created bioprinted 3D-models of ES cell lines and of cells obtained from ES PDXs, using extrusion bioprinting techniques (where cells are encapsulated within the cross-linked polymers, thus allowing homogeneous distribution and high cell density). PDX-derived cells were kept in liquid culture and as 3D-bioprinted constructs, while their transcription profiles were compared with the initial PDX. The mevalonate pathway was the most overrepresented in all ES 3D-models, consistent with predominant upregulation of this metabolic pathway integral to tumor growth and progression. After 15 days in 3D-bioprinted culture, we observed pronounced upregulation of genes involved in ECM signaling, suggesting that the construct promoted in vivo-like tumor-ECM interactions, without further promoting main proliferation and cell survival pathways, which was observed in liquid culture. Furthermore, we showed potential for combinatorial treatment with statins and confirmed feasibility of drug testing in patient-derived 3D models. Finally, as our spheroid models showed upregulation of many processes involved in metastasis (genes associated with invasion, migration, angiogenesis