Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

Schott, C. R.; Koehne, A. L.; Sayles, L. C.; Young, E. P.; Luck, C.; Yu, K.; Lee, A. G.; Breese, M. R.; Leung, S. G.; Shah, A. T.; Xu, H.; Liu, H.-Y.; Spillinger, A.; Behroozfard, I. H.; Marini, K. D.; Dinh, P. T.; Pons Ventura, M. V.; Vanderboon, E. N.; Hazard, F. K.; Cho, S.-J.; Avedian, R. S.; Mohler, D. G.; Zimel, M.; Wustrack, R.; Curtis, C.; Sirota, M.; Sweet-Cordero, E. A.

doi:10.1101/2023.01.19.524562

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bioRxiv · 10.1101/2023.01.19.524562

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

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Abstract

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/524562v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17ea2a8org.highwire.dtl.DTLVardef@e8fcc7org.highwire.dtl.DTLVardef@2b9f8corg.highwire.dtl.DTLVardef@1f7b802_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Schott, C. R., Koehne, A. L., Sayles, L. C., Young, E. P., Luck, C., Yu, K., Lee, A. G., Breese, M. R., Leung, S. G., Shah, A. T., Xu, H., Liu, H.-Y., Spillinger, A., Behroozfard, I. H., Marini, K. D., Dinh, P. T., Pons Ventura, M. V., Vanderboon, E. N., Hazard, F. K., Cho, S.-J., Avedian, R. S., Mohler, D. G., Zimel, M., Wustrack, R., Curtis, C., Sirota, M., Sweet-Cordero, E. A.. 2023-01-20. Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities. https://doi.org/10.1101/2023.01.19.524562

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