Lu Yunfei, Chen Yang, Wang Zhenling, Shen Hengyang, Xu Lei, Huang Changzhi, Tong Ying, Shao Yu, Zhang Hongqiang, Fu Zan
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
The First College of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
J Transl Med. 2025 Mar 6;23(1):282. doi: 10.1186/s12967-025-06236-5.
Cancer-associated fibroblasts (CAFs), known for facilitating the progression and metastasis of colorectal cancer (CRC), have become a promising therapeutic target. However, the significant heterogeneity of CAFs and their intricate crosstalk with tumor cells present substantial challenges in the development of precise and effective therapeutic strategies.
Single-cell RNA sequencing (scRNA-seq) technology was used to identify various cell subtypes. Spatial transcriptomics (ST) was employed to map the spatial niches and colocalization patterns of these cell subtypes. Cell-cell interactions among these subtypes were analysed via CellChat and NicheNet software. Tumor cell invasion, migration, and proliferation were assessed through wound healing assays, transwell assays, colony formation assays, and xenograft mouse models.
We identified a significant spatial colocalization between CTHRC1+ CAFs and a distinct subtype of malignant epithelial cells, both residing within the EMT-active spatial niche. Our results demonstrate that CTHRC1+ CAFs, as a major source of WNT5A, promote epithelial-mesenchymal transition (EMT) and enhance tumor cell invasiveness by upregulating MSLN expression in adjacent malignant epithelial cells. This signaling axis contributes significantly to CRC progression and metastasis.
Targeting the CTHRC1+ CAF-WNT5A-MSLN signaling axis presents a promising therapeutic strategy for advanced CRC patients. Our study provides new insights into the role of CAFs in CRC progression and offers potential avenues for developing targeted therapies to disrupt this pathway.
癌症相关成纤维细胞（CAFs）以促进结直肠癌（CRC）的进展和转移而闻名，已成为一个有前景的治疗靶点。然而，CAFs的显著异质性及其与肿瘤细胞的复杂相互作用给精确有效的治疗策略的开发带来了重大挑战。
使用单细胞RNA测序（scRNA-seq）技术来识别各种细胞亚型。采用空间转录组学（ST）来绘制这些细胞亚型的空间生态位和共定位模式。通过CellChat和NicheNet软件分析这些亚型之间的细胞-细胞相互作用。通过伤口愈合试验、Transwell试验、集落形成试验和异种移植小鼠模型评估肿瘤细胞的侵袭、迁移和增殖。
我们发现CTHRC1+ CAFs与一种独特的恶性上皮细胞亚型之间存在显著的空间共定位，两者都存在于EMT活跃的空间生态位内。我们的结果表明，CTHRC1+ CAFs作为WNT5A的主要来源，通过上调相邻恶性上皮细胞中的MSLN表达促进上皮-间质转化（EMT）并增强肿瘤细胞的侵袭性。该信号轴对CRC的进展和转移有显著贡献。
靶向CTHRC1+ CAF-WNT5A-MSLN信号轴为晚期CRC患者提供了一种有前景的治疗策略。我们的研究为CAFs在CRC进展中的作用提供了新的见解，并为开发靶向疗法以破坏该途径提供了潜在途径。
