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

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.

Patterns of metastatic progression and association with clinical outcomes in canine osteosarcoma: A necropsy study of 83 dogs

“…The clinical, molecular, and biological similarities between canine and human osteosarcoma make dogs an excellent patient model for studying patterns of metastatic progression 8,9 . Laboratory experiments, typically involving in vitro/ex vivo systems and/or mouse models, often fail to replicate the complexity of tumour–host interactions and risk factors associated with naturally occurring human malignancies 10–14 . The prevalence of osteosarcoma in pet dogs offers a solution to this limitation, with dogs' relatively short life spans and intact, educated immune systems allowing researchers to study human diseases at a biologically accelerated rate 14 .…”

“…8,9 Laboratory experiments, typically involving in vitro/ex vivo systems and/or mouse models, often fail to replicate the complexity of tumour-host interactions and risk factors associated with naturally occurring human malignancies. [10][11][12][13][14] The prevalence of osteosarcoma in pet dogs offers a solution to this limitation, with dogs' relatively short life spans and intact, educated immune systems allowing researchers to study human diseases at a biologically accelerated rate. 14 The NCI's Comparative Oncology programme utilises this unique aspect of canines to conduct experimental studies through a national partnership of veterinary schools known as the Comparative Oncology Trial Consortium (COTC).…”