A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.
A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.
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DOI：
10.1016/j.canlet.2016.09.001
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发表时间：
2016-11-28
期刊：
影响因子：
9.7
通讯作者：
Orsulic, Sandra
中科院分区：
文献类型：
--
作者：
Jia, Dongyu;Liu, Zhenqiu;Deng, Nan;Tan, Tuan Zea;Huang, Ruby Yun-Ju;Taylor-Harding, Barbie;Cheon, Dong-Joo;Lawrenson, Kate;Wiedemeyer, Wolf R.;Walts, Ann E.;Karlan, Beth Y.;Orsulic, Sandra
虽然癌症相关成纤维细胞（CAFs）被视为一个有前途的治疗靶点，但合理治疗的设计受到两个关键障碍的阻碍。首先，消融CAF的尝试已经导致显著的毒性，因为目前使用的生物标志物不能有效区分活化的CAF与非癌症相关的成纤维细胞和间充质祖细胞。其次，目前还不清楚不同器官中的CAFs是否具有不同的分子和功能特性，这些特性需要器官特异性治疗设计。我们的分析揭示了COL11A1作为活化CAFs的高度特异性生物标志物。使用COL11A1作为“种子”，我们在癌症基因组图谱中确定了13种原发性癌症中的共表达基因。我们证明了激活的CAF的分子特征在上皮癌中是保守的，而不管癌细胞内的器官部位和转化事件如何，这表明靶向成纤维细胞激活在多种癌症中应该是有效的。我们优先考虑了几个潜在的泛癌症治疗靶点，这些靶点可能对激活的CAF具有高特异性，并且在正常组织中具有最小的毒性。
Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs. Our analyses uncovered COL11A1 as a highly specific biomarker of activated CAFs. Using COL11A1 as a ‘seed’, we identified co-expressed genes in 13 types of primary carcinoma in The Cancer Genome Atlas. We demonstrated that a molecular signature of activated CAFs is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, suggesting that targeting fibroblast activation should be effective in multiple cancers. We prioritized several potential pan-cancer therapeutic targets that are likely to have high specificity for activated CAFs and minimal toxicity in normal tissues.
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影响因子：
3.7
作者：
Brentnall TA;Lai LA;Coleman J;Bronner MP;Pan S;Chen R
通讯作者：
Chen R
影响因子：
0.7
作者：
Desmoulière, A;Guyot, C;Gabbiani, C
通讯作者：
Gabbiani, C
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
11.5
作者：
Julien, Sylvia;Merino-Trigo, Ana;Berthet, Cyril
通讯作者：
Berthet, Cyril
影响因子：
10.3
作者：
Gentles, Andrew J.;Bratman, Scott V.;Diehn, Maximilian
通讯作者：
Diehn, Maximilian