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The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids

 Jae-Il Choi  ;  John Hoon Rim  ;  Sung Ill Jang  ;  Joon Seong Park  ;  Hak Park  ;  Jae Hee Cho  ;  Jong-Baeck Lim 
 THERANOSTICS, Vol.12(9) : 4431-4445, 2022-05 
Journal Title
Issue Date
Carcinoma, Pancreatic Ductal* / pathology ; Cell Line, Tumor ; Cell Plasticity ; Endothelial Cells / metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Recurrence, Local / genetics ; Pancreatic Neoplasms* / pathology
Human cancer organoid ; cancer-initiating cells ; plasticity ; tumor microenvironment
Background: Pancreatic ductal adenocarcinoma (PDAC), which commonly relapses due to chemotherapy resistance, has a poor 5-year survival rate (< 10%). The ability of PDAC to dynamically switch between cancer-initiating cell (CIC) and non-CIC states, which is influenced by both internal and external events, has been suggested as a reason for the low drug efficacy. However, cancer cell plasticity using patient-derived PDAC organoids remains poorly understood. Methods: First, we successfully differentiated CICs, which were the main components of PDAC organoids, toward epithelial ductal carcinomas. We further established PDAC assembloids of organoid-derived differentiated ductal cancer cells with endothelial cells (ECs) and autologous immune cells. To investigate the mechanism for PDAC plasticity, we performed single-cell RNA sequencing analysis after culturing the assembloids for 7 days. Results: In the PDAC assembloids, the ECs and immune cells acted as tumor-supporting cells and induced plasticity in the differentiated ductal carcinomas. We also observed that the transcriptome dynamics during PDAC re-programming were related to the WNT/beta-catenin pathway and apoptotic process. Interestingly, we found that WNT5B in the ECs was highly expressed by trans interaction with a JAG1. Furthermore, JAG1 was highly expressed on PDAC during differentiation, and NOTCH1/NOTCH2 were expressed on the ECs at the same time. The WNT5B expression level correlated positively with those of JAG1, NOTCH1, and NOTCH2, and high JAG1 expression correlated with poor survival. Additionally, we experimentally demonstrated that neutralizing JAG1 inhibited cancer cell plasticity. Conclusions: Our results indicate that JAG1 on PDAC plays a critical role in cancer cell plasticity and maintenance of tumor heterogeneity.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Joon Seong(박준성) ORCID logo https://orcid.org/0000-0001-8048-9990
Park, Hak(박학) ORCID logo https://orcid.org/0000-0002-1817-3167
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Lim, Jong Baeck(임종백) ORCID logo https://orcid.org/0000-0003-0419-0422
Jang, Sung Ill(장성일) ORCID logo https://orcid.org/0000-0003-4937-6167
Cho, Jae Hee(조재희) ORCID logo https://orcid.org/0000-0003-4174-0091
Choi, Jae-Il(최재일)
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