An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer.
An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer.
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DOI：
10.15252/msb.20177739
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发表时间：
2017-12-01
影响因子：
9.9
通讯作者：
Ruppin E
中科院分区：
文献类型：
--
作者：
Auslander N;Cunningham CE;Toosi BM;McEwen EJ;Yizhak K;Vizeacoumar FS;Parameswaran S;Gonen N;Freywald T;Bhanumathy KK;Freywald A;Vizeacoumar FJ;Ruppin E
代谢改变在癌症中发挥着重要作用，然而，我们所知的代谢癌症驱动基因却很少。在这里，我们进行了组合的基因组和代谢建模分析，寻找结直肠癌的代谢驱动因素。我们的分析预测 FUT9（催化 Ley 糖脂的生物合成）是晚期结肠癌的驱动因素。实验测试揭示了 FUT9 复杂的双重作用；虽然它的敲除增强了单层细胞的增殖和迁移，但它抑制了结肠癌细胞在肿瘤球中的扩张，并抑制了小鼠异种移植模型中的肿瘤发展。这些结果表明，FUT9 的抑制作用可能会减弱已知主导肿瘤球和早期肿瘤生长的肿瘤起始细胞 (TIC)，但会促进大量肿瘤细胞的生长。一致地，我们发现 FUT9 沉默会降低结直肠癌 TIC 标记物 CD44 的表达和 OCT4 转录因子的水平，而 OCT4 转录因子已知支持癌症干细胞性。除了当前的应用之外，这项工作还提出了一种新颖的基因组和代谢建模计算方法，可以促进其他类型癌症中代谢驱动基因的系统发现。
Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced‐stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor‐initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.5
作者：
Alazzouzi, H;Alhopuro, P;Arango, D
通讯作者：
Arango, D
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
5.3
作者：
Cheng X;O'Neill HC
通讯作者：
O'Neill HC