PO.MCB06.03 · 分子与细胞生物学
染色质可及性区分胰腺癌中的癌症相关成纤维细胞亚型
Chromatin accessibility differentiates cancer associated fibroblast subtypes in pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）仍是致死率最高的癌症，患者五年生存率仅为13%。然而，由于PDAC肿瘤微环境中致密的纤维化基质，有效的药物递送及免疫治疗的实施受到限制，而该基质主要由癌症相关成纤维细胞（CAF）构成。遗憾的是，由于对CAF的激活、异质性及可塑性缺乏了解，靶向CAF以增强PDAC治疗迄今尚未成功。既往scRNA-seq研究揭示了具有多样表型及功能的不同CAF亚型，但CAF激活的潜在机制仍不明确。值得注意的是，CAF与其起源细胞在遗传学上并无差异，且它们可依外部因素及信号线索相互转化。这一可塑性特征表明CAF的特征在于其细胞状态，而非终点分化。因此，我们假设CAF激活受表观遗传重编程调控。利用ATAC-seq及创新的PDAC类器官-CAF共培养模型，我们在体外揭示了两种主要CAF亚型——肌成纤维细胞及炎症性成纤维细胞——各自不同的染色质可及性谱。我们在全基因组范围鉴定出获得性差异可及区域，这些区域不仅位于启动子，也位于增强子，且与各亚型的转录特征高度相关。与此一致，对人类患者及小鼠模型PDAC肿瘤组织内成纤维细胞群体的snATAC-seq分析也证实了不同CAF亚型各自不同的染色质可及性谱。有趣的是，通过与snRNA-seq叠加，我们发现CAF的染色质结构在肿瘤发生过程中被预设为倾向于晚期肌成纤维细胞亚型的可及状态。总之，我们的研究在体外及体内均证明了CAF可塑性的表观遗传基础，提示了一种通过表观遗传靶向CAF以重塑基质并改善PDAC患者治疗结局的新型治疗策略。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) remains the deadliest cancer with only 13% of five-year survival rate in patients. However, effective drug delivery and administration of immunotherapy have been limited due to the dense fibrotic stroma in PDAC tumor microenvironment, majorly contributed by cancer-associated fibroblasts (CAFs). Unfortunately, targeting CAFs to enhance PDAC treatment has not yet been successful due to the lack of understanding in CAF activation, heterogeneity, and plasticity. Previous scRNA-seq studies revealed different CAF subtypes with diverse phenotypes and functions but the underlying mechanisms of CAF activation remain unclear. Of note, CAFs do not genetically differ from their origins, and they are interconvertible depending on external factors and signaling cues. This plasticity feature suggests that CAFs are characterized by their cellular states rather than an end-of-point differentiation. Therefore, we hypothesized that CAFs activation is regulated by epigenetic reprogramming. Using ATAC-seq and innovative PDAC organoid-CAF co-culture models, we revealed distinct chromatin accessibility profiles of two major CAF subtypes, myofibroblasts and inflammatory fibroblasts in vitro . Gained differentially accessible regions were identified across genomes, located not only at promoters but also at enhancers, and they were highly associated with transcriptional signatures of each subtype. In line with this, analysis on snATAC-seq of the fibroblast population within PDAC tumor tissues of both human patients and mouse models also confirmed the distinct chromatin accessibility profiles of different CAF subtypes. Interestingly, by overlaying with snRNA-seq, we discovered that chromatin structure of CAF was primed to be accessible towards late-stage myofibroblast subtype during tumorigenesis. Overall, our study demonstrates the epigenetic basis of CAF plasticity both in vitro and in vivo , suggesting a novel therapeutic strategy of epigenetically targeting CAF to remodel the stroma and improve treatment outcomes in PDAC patients.
利益披露 Disclosure
M. Pham, None..
K. Huang, None.