PO.TB07.03 · 肿瘤生物学
糖尿病相关的成纤维细胞活化作为转移前微环境增强肺转移
Diabetes mellitus related fibroblast activation as a premetastatic niche enhances lung metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
远处转移是癌症预后不良的主要决定因素。流行病学数据表明，糖尿病显著增加胃癌（GC）患者的肺转移（LM）；然而其潜在机制尚不明确。在此，我们报告高糖刺激GC细胞分泌细胞外囊泡（EVs），后者激活肺内的FAP+成纤维细胞，从而建立转移前微环境并增强转移。转录组学和蛋白质组学分析显示，高糖激活FOXM1，促进CEP55转录及其掺入EVs。循环中的CEP55-EVs在肺成纤维细胞中触发CEP55-pFAK-FAP信号通路，驱动其活化。这导致通过分泌tenascin-C进行细胞外基质重塑并形成支架，从而促进GC细胞定植。最后，我们证明抗糖尿病药物格列美脲（glimepiride）抑制成纤维细胞活化并显著减少LM。这些发现揭示了一种由CEP55-EVs介导、糖尿病驱动的LM机制，并提示利用传统抗糖尿病药物抑制LM是一种有效的治疗策略。
查看英文原文 English abstract
Distant metastasis is a major determinant of poor prognosis in cancer. Epidemiological data indicate that diabetes markedly increases lung metastasis (LM) in patients with gastric cancer (GC); however, the underlying mechanisms remain unclear. Here, we report that high glucose stimulates GC cells to secrete extracellular vesicles (EVs) that activate FAP+ fibroblasts in the lung to establish a premetastatic niche and enhance metastasis. Transcriptomic and proteomic analyses revealed that high glucose activates FOXM1, promoting CEP55 transcription and its incorporation into EVs. Circulating CEP55-EVs trigger CEP55-pFAK-FAP signaling in lung fibroblasts, driving their activation. This results in extracellular matrix remodeling by tenascin-C secretion and scaffold formation to facilitate GC cell colonization. Finally, we demonstrate that the antidiabetic drug glimepiride suppresses fibroblast activation and significantly reduces LM. These findings reveal a diabetes-driven mechanism of LM mediated by CEP55-EVs and suggest a potent therapeutic strategy to inhibit LM using conventional antidiabetic drugs
利益披露 Disclosure
L. Fu, None..
T. Ishimoto, None.