Chronic jetlag accelerates pancreatic neoplasia in conditional Kras-mutant mice

Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma – a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated Kras mutation. We found that chronic jetlag accelerated the development of pancreatic cancer precursor lesions, with a concomitant increase in precursor lesion grade. Cell-autonomous knock-out of the clock in pancreatic epithelial cells of Kras-mutant mice demonstrated no acceleration of precursor lesion formation, indicating non-cell-autonomous clock dysfunction was responsible for the expedited tumor development. Therefore, we applied single-cell RNA sequencing over time and identified fibroblasts as the cell population manifesting the greatest clock-dependent changes, with enrichment of specific cancer-associated fibroblast pathways due to circadian misalignment.

生物钟（circadian clock）与环境信号的错配会引发节律紊乱（circadian desynchrony），该现象在人类群体中广泛存在。生物钟错配可诱发多种病理状态，包括肥胖与糖尿病，二者均与胰腺导管腺癌（pancreatic ductal adenocarcinoma）相关——这是一种致死性极强的癌症，五年死亡率高达80%。尽管节律紊乱与多种实体器官肿瘤的发病风险升高存在关联，但生物钟错配与胰腺癌之间的具体关联仍不明确。本研究采用慢性时差模型（chronic jetlag model），探究了生物钟错配对携带胰腺特异性激活型Kras突变（Kras mutation）小鼠的胰腺癌起始进程的影响。研究发现，慢性时差可加速胰腺癌前驱病变的进展，并伴随前驱病变分级的升高。对携带Kras突变小鼠的胰腺上皮细胞进行生物钟的细胞自主性敲除后，并未观察到前驱病变形成加速的现象，这表明非细胞自主性的生物钟功能异常是肿瘤进程加快的诱因。基于此，本研究通过时序性单细胞RNA测序（single-cell RNA sequencing），鉴定出成纤维细胞（fibroblasts）是表现出最大程度生物钟依赖性变化的细胞群，且节律紊乱可引发特定癌相关成纤维细胞（cancer-associated fibroblast）通路的富集。