Jiang Youheng, Fu Zhang, Chen Yanfang, Jin Qunlong, Yang Yanming, Lin Zerong, Li Changxue, Gao Yunfei, Dong Zepeng, He Yang, Mao Xinjun, He Yulong, Zhang Qingyuan, Zhang Qi, Li Ningning
Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
iScience. 2024 Oct 15;27(11):111173. doi: 10.1016/j.isci.2024.111173. eCollection 2024 Nov 15.
Grem1 cancer-associated fibroblasts (CAFs) are crucial in colorectal cancer (CRC) development, yet technical challenges have limited understanding of their origins, spatiotemporal distribution, and potential roles. Here, we devised a custom mold, optimizing the gut Swiss-roll technique to create a single cryopreserved slide for comprehensive staining. Our integrated approach uncovered a marked increase in Grem1 CAFs within mouse tumors at 12 weeks, compared to normal mucosa. Subsequent lineage tracing in ; ; mice revealed that most Grem1 CAFs infiltrating the tumor core originated from Grem1 intestinal reticular stem cells (iRSCs). A minor subset of Grem1 CAFs, located in the submucosa, retained characteristics of Grem1 intestinal sub-epithelial myofibroblasts (ISEMFs). Altogether, CAFs derived from Grem1 iRSCs may serve as a principal stromal cell type driving early-stage CRC progression, while Grem1 ISEMFs contribute less from a more distant location. Hence, targeting Grem1 CAFs presents an early and promising therapeutic strategy in CRC.
Grem1癌相关成纤维细胞（CAFs）在结直肠癌（CRC）发展中至关重要，但技术挑战限制了对其起源、时空分布及潜在作用的了解。在此，我们设计了一种定制模具，优化肠道瑞士卷技术以创建用于全面染色的单个冷冻保存玻片。我们的综合方法发现，与正常黏膜相比，在12周时小鼠肿瘤内Grem1 CAFs显著增加。随后在;;;;小鼠中的谱系追踪显示，浸润肿瘤核心的大多数Grem1 CAFs起源于Grem1肠道网状干细胞（iRSCs）。位于黏膜下层的一小部分Grem1 CAFs保留了Grem1肠道上皮下肌成纤维细胞（ISEMFs）的特征。总体而言，源自Grem1 iRSCs的CAFs可能作为驱动早期CRC进展的主要基质细胞类型，而Grem1 ISEMFs从更远距离的贡献较小。因此，靶向Grem1 CAFs在CRC中是一种早期且有前景的治疗策略。
