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Ewing sarcoma (EwS) is a highly malignant bone and soft tissue tumor primarily affecting children and young adults. While most patients initially respond well to conventional front-line therapy, frequent metastasis results in poor 5-year overall survival rates for this disease. Accordingly, there is a critical need to develop better models to understand EwS metastasis. We and others previously used the ex vivo pulmonary metastasis assay (PuMA) to study lung metastasis in solid tumors including osteosarcoma (OS), but this technique has to date not been achievable for EwS. PuMA involves tail vein injection of fluorescent tumor cells into NOD-SCID mice, followed by their visualization in long-term cultures of tumor-bearing lung explants. Here we demonstrate successful implementation of PuMA for EwS cells using NOD-SCID-IL2 receptor gamma null (NSG) immunocompromised mice, which demonstrated high engraftment of EwS cell lines compared to NOD-SCID mice. This may be linked to immune permissiveness required by EwS cells, as increased basal cytotoxicity of EwS cells was observed in NOD-SCID compared to NSG lung sections, possibly due to the absence of natural killer (NK) cell activity in the latter. Together, our data demonstrate the utility of NSG mice for PuMA modeling of EwS lung metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Scopim-Ribeiro, Lizardo, Zhang, Dhez, Hughes and Sorensen.)

Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease progression as occurs in humans. Pet dogs can be leveraged for the exploration of novel therapies that exploit tumor cell vulnerabilities, perturb local microenvironmental cues, and amplify immunologic recognition. In this capacity, pet dogs can serve as valuable corroborative models for realizing the science and best clinical practices necessary for understanding and combating osteosarcoma metastases., (Copyright © 2020 Fan, Roberts and Lizardo.)