神经酰胺合成通过 YAP 驱动的再生程序介导结直肠癌转移
Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program
研究要解决的问题是：原发肿瘤细胞如何通过代谢和信号改变获得转移能力，此前并不清楚。作者发现，膳食脂肪会持续增强肿瘤细胞内的神经酰胺从头合成（一种脂质合成过程），关键酶是 Degs1。蓄积的神经酰胺通过蛋白磷酸酶 2A 使 YAP 蛋白去磷酸化而被激活，从而让肿瘤细胞转向一种持久的“YAP 驱动的再生程序”，以 Basp1 为标志，促进转移。清除 Basp1 高表达的癌细胞可阻止转移灶形成；缺失 Degs1 则降低神经酰胺、YAP 活性、再生程序标志和转移，但不影响原发肿瘤生长。这提示神经酰胺-YAP 信号是转移启动的关键环节，且独立于原发肿瘤增大，可能成为抗转移的新靶点。
为什么推荐给您：揭示膳食脂肪-神经酰胺-YAP 驱动转移的新机制，具明确转化前景，但主要基于动物与细胞实验
不需要生物学背景，多打比方
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摘要Abstract
Mechanisms by which primary tumor cells acquire metastatic capability through metabolic and signaling adaptations are currently poorly understood. We demonstrate that tumor-intrinsic ceramide metabolism, amplified by dietary fat, initiates colorectal cancer metastasis. We observed that dietary fat exposure triggers a sustained increase in de novo ceramide biosynthesis, mediated by the dihydroceramide desaturase Degs1. Ceramide accumulation activates yes-associated protein (YAP) through protein phosphatase 2A (PP2A)-mediated dephosphorylation, promoting a durable shift toward a distinct YAP-driven regenerative (YAP-DR) program, marked by Basp1, that promotes metastasis. Selective elimination of Basp1high cancer cells prevented metastatic seeding. Degs1 loss reduced ceramide levels, YAP activity, YAP-DR signatures, and metastasis without affecting primary tumor growth, whereas blocking ceramide degradation enhanced YAP activity and metastasis. These findings identify ceramide-induced YAP signaling as a key mediator of metastatic initiation, operating independently of primary tumor expansion.