Profiling of conditionally reprogrammed cell lines for in vitro chemotherapy response prediction of pancreatic cancer
Hee Seung Lee,
Eunyoung Kim,
Jinyoung Lee,
Seung Joon Park,
Ho Kyoung Hwang,
Chan Hee Park,
Se-Young Jo,
Chang Moo Kang,
Seung-Mo Hong,
Huapyong Kang,
Jung Hyun Jo,
In Rae Cho,
Moon Jae Chung,
Jeong Youp Park,
Seung Woo Park,
Si Young Song,
Jung Min Han,
Sangwoo Kim,
Seungmin Bang
Affiliations
Hee Seung Lee
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Eunyoung Kim
Department of Biomedical Systems Informatics and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Jinyoung Lee
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Seung Joon Park
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea
Ho Kyoung Hwang
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
Chan Hee Park
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Se-Young Jo
Department of Biomedical Systems Informatics and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Chang Moo Kang
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
Seung-Mo Hong
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Huapyong Kang
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Jung Hyun Jo
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
In Rae Cho
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Moon Jae Chung
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Jeong Youp Park
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Seung Woo Park
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Si Young Song
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
Jung Min Han
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea; Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea
Sangwoo Kim
Department of Biomedical Systems Informatics and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea; Corresponding authors.
Seungmin Bang
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea; Corresponding authors.
Background: The establishment of patient-derived models for pancreatic ductal adenocarcinoma (PDAC) using conventional methods has been fraught with low success rate, mainly because of the small number of tumour cells and dense fibrotic stroma. Here, we sought to establish patient-derived model of PDAC and perform genetic analysis with responses to anticancer drug by using the conditionally reprogrammed cell (CRC) methodology. Methods: We performed in vitro and in vivo tumourigenicity assays and analysed histological characteristics by immunostaining. We investigated genetic profiles including mutation patterns and copy number variations using targeted deep sequencing and copy-number analyses. We assessed the responses of cultured CRCs to the available clinical anticancer drugs based on patient responsiveness. Findings: We established a total of 28 CRCs from patients. Of the 28 samples, 27 showed KRAS mutations in codon 12/13 or codon 61. We found that somatic mutations were shared in the primary-CRC pairs and shared mutations included key oncogenic mutations such as KRAS (9 pairs), TP53 (8 pairs), and SMAD4 (3 pairs). Overall, CRCs preserved the genetic characteristics of primary tumours with high concordance, with additional confirmation of low-AF NPM1 mutation in CRC (35 shared mutations out of 36 total, concordance rate=97.2%). CRCs of the responder group were more sensitive to anticancer agents than those of the non-responder group (P < 0.001). Interpretation: These results show that a pancreatic cancer cell line model can be efficiently established using the CRC methodology, to better support a personalized therapeutic approach for pancreatic cancer patients. Funding: 2014R1A1A1006272, HI19C0642-060019, 2019R1A2C2008050, 2020R1A2C209958611, and 2020M3E5E204028211
