Tao Mengyu, Liu Wenting, Chen Jianhua, Liu Rujiao, Zou Jianling, Yu Bo, Wang Chenchen, Huang Mingzhu, Chen Qingjian, Zhang Zhe, Chen Zhiyu, Sun Haoyu, Zhou Cheng, Tan Shuguang, Zheng Yuxuan, Wang Hongxia
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200800, P. R. China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
Adv Sci (Weinh). 2025 May;12(20):e2415196. doi: 10.1002/advs.202415196. Epub 2025 Feb 28.
Cancer-associated fibroblasts (CAFs) play a crucial role in the progression of pancreatic ductal adenocarcinoma (PDAC). Here, integrated single-cell RNA sequencing analysis is utilized to comprehensively map CAFs in the human PDAC tumor microenvironment (TME). Normal fibroblasts (NFs) and nine distinct CAF subtypes are identified including newly identified CAF subtypes, CDCP1FTL CAFs, transitional CAFs (tCAFs), interferon simulated genes (ISG) myofibroblastic CAFs (myCAFs), and proliferative CAFs (pCAFs). CDCP1FTL CAFs, pCAFs, and ISG myCAFs are associated with unfavorable clinical outcomes. CDCP1FTL CAFs exhibit enhanced glycolysis and iron metabolism, resisting ferroptosis. The antigen-presenting CAFs (apCAFs) show high heterogeneity, consisting of multiple subtypes expressing distinct immune cell signatures. The CAF subtypes display differentiation plasticity, transitioning from early normal-like CAFs (nCAFs) to inflammatory CAFs (iCAFs) and myCAFs, ultimately leading to more invasive pCAFs. AP-1 family members FOS and JUN regulate the malignant phenotype conversion of NFs to nCAFs, while transforming growth factor-β (TGFβ) and interferon-γ (IFNγ) signals trigger the interconversion between classic myCAFs and iCAFs, respectively. A close interaction between CAFs and myeloid cells (especially neutrophils) is further observed in PDAC-TME, mainly mediated by CXCR4-CXCL12 chemotaxis. This work depicts a detailed CAF map and its dynamic interconvertible shift, providing important insights for combined targeted CAFs therapy.
癌症相关成纤维细胞（CAFs）在胰腺导管腺癌（PDAC）的进展中起着关键作用。在此，利用整合单细胞RNA测序分析全面描绘人类PDAC肿瘤微环境（TME）中的CAFs。鉴定出正常成纤维细胞（NFs）和九种不同的CAF亚型，包括新鉴定的CAF亚型、CDCP1FTL CAFs、过渡性CAFs（tCAFs）、干扰素模拟基因（ISG）肌成纤维细胞CAFs（myCAFs）和增殖性CAFs（pCAFs）。CDCP1FTL CAFs、pCAFs和ISG myCAFs与不良临床结局相关。CDCP1FTL CAFs表现出增强的糖酵解和铁代谢，抵抗铁死亡。抗原呈递CAFs（apCAFs）表现出高度异质性，由表达不同免疫细胞特征的多个亚型组成。CAF亚型表现出分化可塑性，从早期正常样CAFs（nCAFs）转变为炎症性CAFs（iCAFs）和myCAFs，最终导致更具侵袭性的pCAFs。AP-1家族成员FOS和JUN调节NFs向nCAFs的恶性表型转化，而转化生长因子-β（TGFβ）和干扰素-γ（IFNγ）信号分别触发经典myCAFs和iCAFs之间的相互转化。在PDAC-TME中进一步观察到CAFs与髓系细胞（尤其是中性粒细胞）之间的密切相互作用，主要由CXCR4-CXCL12趋化作用介导。这项工作描绘了详细的CAF图谱及其动态可相互转换的转变，为联合靶向CAFs治疗提供了重要见解。
