Introduction

Osteosarcoma, the most common primary bone tumor in both dogs and humans, has a guarded prognosis. A major hurdle in developing more effective therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo.

Methods

We developed a method using a xenograft model to distinguish tumor-derived from host-response exosomal mRNAs, allowing for identification of canine osteosarcoma-specific gene signatures by RNAseq and a species-differentiating bioinformatics pipeline.

Results

An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by qRT-PCR with machine learning. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups (“healthy,” “osteosarcoma,” “other bone tumor,” or “non-neoplastic disease”). Pre-treatment samples from osteosarcoma cases were used as the training set and a validation set from post-treatment samples was used for testing, classifying as “osteosarcoma-detected” or “osteosarcoma-NOT detected.” Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma-NOT detected” had longer remissions, up to 15 months after treatment.

Conclusion

We identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof-of-concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.

Funding Information

Request information from author.