Carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, the existence and genetic alternations of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. The establishment of xenograft model using CTCs should help us to understand the biologic behaviors and genetic alternations of MICs associated the promotion of metastasis. Here, we demonstrate that xenograft model can be established by CTCs obtained from lung cancer patients and somatic mutations analyzed from xenograft model in which MICs develop metastatic tumor. After injecting mononuclear cells of lung cancer patients via tail vein, mouse was sacrificed at four weeks. After primary cultured cells were isolated from mouse lung tissues, the MICs were selected by using FASC sorting (EpCam+) and then re-injected via tail vein. And tumor formations in mouse were examined at 8 weeks. For identifying somatic mutations, target sequencing with NGS was performed in tumor DNA and cell free DNA (CF DNA) of lung cancer patients bloods. Our results indicated that nonsynonymous IDH, EGFR, KIT, ABL1, PTEN, ATM, P53, and SMAD4 were found in both tumor tissues and CF DNA of lung cancer patients’ bloods. IDH and EGFR was alternative homo. Others newly found in CF DNA. For further examination of the biologic behaviors of tumor cells which harvested from xenograft model using CTCs, we cultured primary cells from lung tissues and analyzed the anti-cancer drug resistance. Our results showed that primary cultured cells (BH-007) were resistant against cisplatin and erlotinib. In assay of migration and invasion, BH-007 cells possessed high metastatic potential when compared with A549 and H23 cell lines. These data suggested that several somatic mutations affect the anti-cancer drug resistance in lung cancer patients. Our future researches will include development of patient-derived xenograft models for preclinical testing of novel therapeutics. And we develop the possible integration of CF DNA analysis and PDX model from CTCs in the design of co-clinical studies for testing in individual lung cancer patients.
Citation Format: Chansu Lee, Youngwook Kim, Eunkyung Bae, Sunghoon Cho, Sohyun Youn, Kwang-Sung Ahn, Bong-Seog Kim. Establishment of lung cancer patient derived xenograft model from circulating tumor cells: Identification of somatic mutations associated with metastatic potentials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 77.