Development and characterisation of a large animal transgenic tumor model for sarcomatoid renal cell carcinoma

Background Sarcomatoid (and rhabdoid) dedifferentiation can occur in similar to 5% of renal cell carcinomas (sRCC), a finding with significant therapeutic implications. sRCC is associated with increased aggressiveness, resistance to conventional targeted therapies, and increased sensitivity to immune checkpoint inhibitors.Objective There are no preclinical models for sRCC that can be used in research to better understand this disease. The pig has similar size, anatomy, immune system, and genetics, that can be employed to evaluate procedures or tumor specific drugs. We report on the creation of a large animal porcine model for sRCC.Materials In eight Oncopigs, a Cre-recombinase gene adenoviral vector (AdCre) was incubated with renal tissue obtained from an ultrasound (US) percutaneous biopsy and reinjected into the renal cortex. US was performed to assess growth and to obtain tumor tissue for pathologic and immunohistochemistry evaluation.Results Three weeks post inoculation renal tumors were successfully formed in 28 out of 32 sites (88%). Mean tumor size by imaging was 1.6 x 1.1 cm (range: 0.4-3.9 cm longest axis). Pigs remained clinically healthy up to 25 days after inoculation. On histology, tumors consisted of foci of infiltrating sarcomatoid and rhabdoid cells in a background of marked acute and chronic inflammation. The neoplastic cells showed positive immunoreactivity for PAX8, cytokeratin AE1/AE3 supporting a renal tubular origin. These cells were diffusely positive for p53 and showed high ki-67 (20-30%), and cleaved caspase 3 (20-30%) expression.Conclusion Rapid growing poorly differentiated neoplasms associated with a marked inflammatory reaction that have phenotypic and immunohistochemical features of sRCC were successfully developed. These may be suitable to study the response to local and systemic therapies.