The Canonical Wnt Pathway Drives Macropinocytosis in Cancer.
The Canonical Wnt Pathway Drives Macropinocytosis in Cancer.
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DOI：
10.1158/0008-5472.can-17-3199
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发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Glickman MS
中科院分区：
文献类型：
--
作者：
Redelman-Sidi G;Binyamin A;Gaeta I;Palm W;Thompson CB;Romesser PB;Lowe SW;Bagul M;Doench JG;Root DE;Glickman MS
巨胞饮已经成为癌细胞中蛋白质获取的重要途径，特别是在具有活化Ras的肿瘤如胰腺癌和结肠癌中。巨胞饮作用也是卡介苗（BCG）和其他癌症微生物疗法的进入途径。尽管在肿瘤生物学和治疗中起着重要作用，但癌细胞激活巨胞饮的全部机制仍不完全确定。使用BCG摄取来测定巨胞饮，我们对巨胞饮激活剂进行了全基因组shRNA筛选，并将Wnt途径激活确定为巨胞饮的强驱动因素。Wnt驱动的巨胞饮是β连环蛋白依赖性经典Wnt通路的下游，是Pak 1依赖性的，并支持Ras-WT细胞中的白蛋白依赖性生长。在具有激活的Ras依赖性巨胞饮的细胞中，Wnt信号传导的药理学或遗传抑制抑制巨胞饮。在通过APC沉默的Wnt驱动的结肠增生的小鼠模型中，Wnt激活的巨胞饮刺激了管腔微生物群的摄取，这一过程被巨胞饮的局部药理学抑制逆转。我们的研究结果表明，Wnt通路激活驱动癌症中的巨胞饮，并且其抑制可以为Wnt驱动的肠息肉病和Wnt激活的癌症提供治疗漏洞。
Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the beta catenin-dependent canonical Wnt pathway, was Pak1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation.