Construction of patient-derived xenograft model aimed at overcoming pulmonary metastases of pediatric malignant solid tumor

Abstract

Although treatment outcomes for pediatric malignant solid tumors have improved, the prognosis of patients with metastases is often poor. Although we are surgically removing lung metastases, surgery alone is often insufficient, and the development of new treatments is highly desired. Therefore, to develop a research platform close to actual clinical settings and to develop a treatment method using such a platform, we constructed a patient-derived xenograft (PDX) model by transplanting the resected lung metastases into immunodeficient mice. A study using this lung metastasis model has begun. Fourteen lung metastatic specimens (including pleural dissemination) were subcutaneously transplanted into NSG mice, and 12 were successfully established. The types of tumor (number of tumor specimens successfully established/number of transplants) were osteosarcoma (6/6), hepatoblastoma (1/2), Ewing’s sarcoma (1/1), malignant myoepithelial tumor (1/1), malignant rhabdoid tumor (1/1), hepatocellular carcinoma (1/2), and yolk sac tumor (1/1). The engraftment rate of PDX is generally not high, but the use of lung metastatic specimens may contribute to our high success rate of establishment. For osteosarcoma and Ewing’s sarcoma, we succeeded in generating a lung metastasis model by dispersing subcutaneous PDX in a protease cocktail and injecting it into the tail vein of mice. Taking advantage of the PDX characteristics that the tumor cells are from humans and the interstitial cells are from mice, the mouse and human transcriptomes can be evaluated separately for each PDX. We are proceeding with gene expression analysis with the aim of developing new therapeutic methods specialized for lung metastasis from the viewpoint of tumor microenvironment.