Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Institute of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Theranostics. 2022 May 24;12(9):4431-4445. doi: 10.7150/thno.71364. eCollection 2022.
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. 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. 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. Our results indicate that JAG1 on PDAC plays a critical role in cancer cell plasticity and maintenance of tumor heterogeneity.
胰腺导管腺癌（PDAC）常因化疗耐药而复发，其 5 年生存率较低（<10%）。PDAC 能够在癌症起始细胞（CIC）和非 CIC 状态之间动态切换，这种状态受到内外因素的影响，这被认为是药物疗效低的一个原因。然而，利用患者来源的 PDAC 类器官研究癌细胞可塑性的工作仍知之甚少。
首先，我们成功地将 PDAC 类器官的主要成分 CIC 分化为上皮导管癌。我们进一步建立了由类器官衍生的分化导管癌细胞与内皮细胞（ECs）和自体免疫细胞组成的 PDAC 组装体。为了研究 PDAC 可塑性的机制，我们在培养组装体 7 天后进行了单细胞 RNA 测序分析。
在 PDAC 组装体中，ECs 和免疫细胞作为肿瘤支持细胞，诱导分化的导管癌细胞发生可塑性。我们还观察到，PDAC 重新编程过程中的转录组动力学与 WNT/β-catenin 途径和凋亡过程有关。有趣的是，我们发现 ECs 中的 WNT5B 通过与 JAG1 的相互作用高表达。此外，JAG1 在分化过程中在 PDAC 中高表达，同时 NOTCH1/NOTCH2 在 ECs 中表达。WNT5B 的表达水平与 JAG1、NOTCH1 和 NOTCH2 的表达水平呈正相关，而 JAG1 高表达与预后不良相关。此外，我们通过实验证明了中和 JAG1 可抑制癌细胞可塑性。
我们的研究结果表明，PDAC 上的 JAG1 在癌细胞可塑性和维持肿瘤异质性方面发挥着关键作用。
