PO.TB10.13 · 肿瘤生物学
癌症相关成纤维细胞的施万样重编程重塑胰腺导管腺癌中的肿瘤神经生态位
Schwann like reprogramming of cancer associated fibroblasts remodels the tumor neural niche in pancreatic ductal adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
与其他癌症相比,胰腺导管腺癌(PDAC)的周围神经病变发生率显著更高,这与局部复发及PDAC患者的不良预后相关。值得注意的是,施万细胞——周围神经的主要神经胶质——因其在肿瘤发生和神经重塑中的多方面作用而在此过程中起关键作用。然而,PDAC中施万细胞群增加及整体神经元密度增加的生物学来源在很大程度上仍属未知。在此,我们采用一种结合单细胞RNA测序、免疫荧光和功能实验的整合方法,揭示了PDAC中癌症相关成纤维细胞(CAF)的一种新型神经重编程:成纤维细胞-施万转变(FST),通过该过程一部分CAF直接转分化为施万样状态。FST经拟时序轨迹分析得到证实,该分析显示了从CAF到施万样细胞的细胞命运转变。患者肿瘤的多重免疫荧光鉴定出共表达经典施万细胞和CAF标志物的过渡界面细胞,这与计算推断一致。此外,在肿瘤细胞与CAF的共培养中,CAF发展出施万样特征,伴随施万细胞基因的上调,凸显了它们深刻的可塑性。为查明该过程的调控驱动因素,SCENIC分析鉴定出关键的成纤维细胞特异性转录因子作为FST程序的关键调节因子。此外,通过在CAF中过表达候选转录因子在体外诱导出施万样表型,表现为CAF相关基因表达降低及施万细胞标志物增加。总体而言,我们的发现提示FST是一个与PDAC中观察到的神经元密度增加相关的生物学过程。本研究鉴定出肿瘤微环境中一种此前未知的细胞可塑性机制,并提出靶向FST可能是治疗PDAC周围神经病变的一种潜在治疗策略。本工作由香港研究资助局主题研究计划(编号T12-201/20-R,中国香港)、香港优配研究金(编号12102722,中国香港)及2020年广东省科技创新战略专项资金(编号2020B1212030006,中国广东)资助。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) has a significantly higher incidence of peripheral neuropathy compared to other cancers, which is associated with local recurrence and a poor prognosis for PDAC patients. Notably, Schwann cells, the principal glia of peripheral nerves, are critically involved in this process due to their multifaceted roles in tumorigenesis and neural remodeling. Nevertheless, the biological sources of the increased Schwann cell population and overall increased neuronal density in PDAC are still mainly unknown. Here by employing an integrative approach combining single-cell RNA sequencing, immunofluorescence, and functional assays, we revealed a novel neural reprogramming of cancer-associated fibroblasts (CAFs) in PDAC: the Fibroblast-Schwann Transition (FST), through which a subset of CAFs directly transdifferentiates into Schwann-like states. The FST was confirmed by pseudotime trajectory analysis, which showed a cell fate transition from CAFs to Schwann-like cells. Multiplex immunofluorescence of patient tumors identified transitional interface cells co-expressing canonical Schwann and CAF markers, which is consistent with the computational inference. Furthermore, in the co-culture of tumor cells and CAFs, CAFs developed Schwann-like features, with upregulation of Schwann-cell genes, highlighting their profound plasticity. To figure out the regulatory driver of this process, SCENIC analysis identified key fibroblast-specific transcription factors as critical regulators of the FST program. Additionally, a Schwann-like phenotype was induced in vitro by overexpressing the candidate transcription factor in CAFs, as evidenced by decreased CAF-associated gene expression and increased Schwann-cell markers.Overall, our findings suggest that the FST is a biological process associated with the increased neuronal density observed in PDAC. This study identifies a previously unknown cellular plasticity mechanism in the tumor microenvironment and proposes that targeting FST could be a potential therapeutic strategy for treating peripheral neuropathy in PDAC.This work is supported by the Hong Kong RGC Theme-based Research Scheme (No. T12-201/20-R, HongKong, China), Hong Kong General Research Fund (No. 12102722, HongKong, China), and the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (No. 2020B1212030006, GuangDong, China).
利益披露 Disclosure
L. Yang, None..
X. Cui, None..
S. Qiao, None..
Y. He, None..
Z. Su, None..
Z. Chen, None..
F. Ding, None..
A. Lu, None..
F. Li, None.