Establishment of patient-derived xenografts for neuroendocrine tumors in the avian embryo model.

Abstract

Elucidating the mechanisms underlying cancer progression and identifying tailored therapies for patients can be enhanced by using patient-derived preclinical models. In this study, we investigated whether patient-derived xenograft (PDX) models of well-differentiated neuroendocrine tumors (NETs) could be established in the avian embryo ex ovo model. We found that fresh surgical tumor samples from well-differentiated primary small-intestine and pancreatic NETs, as well as metastatic sites, exhibited engraftment rates exceeding 80% in the avian embryo model. The NET PDXs in the avian model preserved the distinct histological features of NETs, including characteristic tumor nests and the 'salt and pepper' chromatin pattern in nuclei. Using immunostaining, we showed that the engrafted patient tumor fragments remained viable and maintained the proliferation rate, e.g. tumor grade, of the corresponding patient tumors. The NET PDXs continued to express characteristic neuroendocrine markers, such as the insulinoma-associated 1 (INSM1) transcription factor and chromogranin A (CgA). Importantly, they also retained the patient's somatostatin receptor 2 (SSTR2) expression pattern in cancer cells, which is the target of radioligand therapy. Using high-frequency ultrasound imaging and immunostaining, we also demonstrated that the engrafted tumor specimens were vascularized and exhibited functional blood perfusion. Overall, this is the first study to demonstrate the feasibility and characterize PDXs of well-differentiated NETs in the avian embryo model.