Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, China.
Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, China; Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
Cell Rep Med. 2024 Jun 18;5(6):101576. doi: 10.1016/j.xcrm.2024.101576. Epub 2024 May 21.
Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.
化疗仍然是治疗晚期食管癌的一线治疗方法。然而，由于难以捉摸的化疗耐药性，只有有限的一部分人能从中获得持久的益处。在这里，我们利用源自食管鳞状细胞癌的患者来源异种移植物（PDX）在临床前环境中研究化疗耐药机制。我们观察到，在对化疗耐药的 PDX 肿瘤微环境中，富含活化的癌相关成纤维细胞（CAFs）。从机制上讲，我们揭示了癌细胞衍生的 S100A8 通过与 CAFs 的 CD147 受体结合触发细胞内 RhoA-ROCK-MLC2-MRTF-A 通路，诱导 CAF 极化并导致化疗耐药。在治疗上，我们证明阻断 S100A8-CD147 通路可以提高化疗效率。在预后方面，我们发现外周血中的 S100A8 水平可以作为化疗反应的指标。总的来说，我们的研究全面了解了食管癌化疗耐药的分子机制，并强调了 S100A8 在食管癌临床管理中的潜在价值。
