Enhancing the translational potential of the ovine pulmonary adenocarcinoma model

Abstract

Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV), resulting in substantial animal welfare concerns and economic losses worldwide. We previously developed a bronchoscopic JSRV catheter instillation technique targeting the cardiac lung lobe that reliably reproduced the spectrum of OPA lesions observed in naturally occurring disease. Beyond its value for investigating JSRV pathogenesis, this experimental system provides a large animal platform for studying human lung cancer. Here, we sought to enhance its translational utility by increasing the number of virus inoculation sites and introducing a novel transbronchial intraparenchymal injection technique. Two-month-old lambs received JSRV at 4 lung sites: the left and right cardiac lobes by bronchoscopic catheter instillation and the left and right ventral diaphragmatic lobes by transbronchial intraparenchymal injection. Disease progression was monitored by monthly computed tomography, with postmortem examination and immunohistochemistry confirming OPA in 17/18 (94%) inoculated sheep. Six sheep (35%) developed advanced OPA, generating 22 gross tumors for translational studies. Bronchoscopic catheter instillation produced larger, faster-growing tumors with increased connective tissue, bronchus-associated lymphoid tissue, and intra-airway fluid, whereas intraparenchymal injection generated smaller, localized lesions. Radiomic analysis further demonstrated distinct tumor evolution between the 2 delivery methods. These findings show that both inoculation techniques are safe and effective, while also producing complementary tumor phenotypes. By increasing tumor yield per animal while generating lesions with differing growth characteristics, this refined OPA model provides a more versatile and translationally relevant platform for lung cancer research, while supporting the reduction in animal use.