Sun Yifeng, Qiao Yina, Niu Yiqi, Madhavan Bindhu Kollivayal, Fang Chao, Hu Jingxiong, Schuck Kathleen, Traub Benno, Friess Helmut, Herr Ingrid, Michalski Christoph W, Kong Bo
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Int J Cancer. 2025 Mar 15;156(6):1272-1281. doi: 10.1002/ijc.35246. Epub 2024 Oct 29.
The ARP2/3 complex, which orchestrates actin cytoskeleton organization and lamellipodia formation, has been implicated in the initiation of pancreatic ductal adenocarcinoma (PDAC). This study aims to clarify its impact on the activity of cancer-associated fibroblasts (CAFs), key players in PDAC progression, and patient outcomes. Early pancreatic carcinogenesis was modeled in p48; LSL-Kras mice with caerulein-induced pancreatitis, complemented by in vitro studies on human immortalized pancreatic stellate cells (PSCs) and primary PDAC-derived CAFs. Data were gained from microarray analysis, RNA sequencing (RNA-seq), and single-cell RNA sequencing (sc-RNA-seq), with subsequent bioinformatics analysis. We uncovered a specific transcriptional signature associated with fibroblast migration in early pancreatic carcinogenesis and linked it to poor survival in patients with PDAC. A pivotal role of the ARP2/3 complex in CAF migration was identified. Inhibition of the ARP2/3 complex markedly decreased CAF motility and induced significant morphological changes in vitro. Furthermore, its inhibition also hindered TGFβ1-mediated myofibroblastic CAF differentiation but had no effect on IL-1-mediated inflammatory CAF differentiation. Our findings position the ARP2/3 complex as central to the migration and differentiation of myofibroblastic CAF. Targeting this complex presents a promising new therapeutic avenue for PDAC treatment.
ARP2/3复合物可协调肌动蛋白细胞骨架组织和片状伪足形成，与胰腺导管腺癌（PDAC）的起始有关。本研究旨在阐明其对癌症相关成纤维细胞（CAFs）活性的影响，CAFs是PDAC进展中的关键参与者，以及对患者预后的影响。在p48；LSL-Kras小鼠中通过雨蛙素诱导的胰腺炎模拟早期胰腺癌发生，并辅以对人永生化胰腺星状细胞（PSCs）和原发性PDAC来源的CAFs的体外研究。数据来自微阵列分析、RNA测序（RNA-seq）和单细胞RNA测序（sc-RNA-seq），并进行后续的生物信息学分析。我们发现了一种与早期胰腺癌发生中与成纤维细胞迁移相关的特定转录特征，并将其与PDAC患者的不良生存联系起来。确定了ARP2/3复合物在CAF迁移中的关键作用。抑制ARP2/3复合物显著降低了CAF的运动能力，并在体外诱导了显著的形态变化。此外，其抑制作用还阻碍了TGFβ1介导的肌成纤维细胞CAF分化，但对IL-1介导的炎性CAF分化没有影响。我们的研究结果表明ARP2/3复合物是肌成纤维细胞CAF迁移和分化的核心。靶向该复合物为PDAC治疗提供了一条有前景的新治疗途径。
