Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells.
Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells.
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DOI：
10.1371/journal.pone.0101777
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kuhn P
中科院分区：
文献类型：
--
作者：
Dago AE;Stepansky A;Carlsson A;Luttgen M;Kendall J;Baslan T;Kolatkar A;Wigler M;Bethel K;Gross ME;Hicks J;Kuhn P
及时描述癌症的演变是预测治疗效果和早期发现耐药性的必要条件。对单个循环肿瘤细胞（CTCs）进行高含量分析，可以在癌症治疗过程中实时地对基因型、形态计量学和蛋白质表达变化进行序列表征。这一概念在一名通过化疗和靶向治疗进展的去势抵抗性前列腺癌患者中进行了研究。在本案例研究中，我们在四个时间点整合了41个全基因组拷贝数变异（CNV）谱、形态计量参数和雄激素受体（AR）蛋白水平。值得注意的是，在标准化疗反应中观察到的变化很小，事实证明，在治疗前后循环中发现了一个独特的克隆(a)，表现出高度重排的CNV谱和AR+表型。然而，靶向治疗后的临床反应和随后的进展与克隆A的急剧减少有关，随后出现了两个不同的CTC亚群，它们在AR基因型和表达表型上都不同。虽然在反应时鉴定出具有平坦或伪二倍体CNV谱的AR-细胞（克隆B），但在复发期间检测到具有CNV谱改变的AR+细胞（克隆C）的新肿瘤谱系。我们发现，尽管克隆C在系统发育上与克隆A相关，但它具有一组独特的体细胞CNV改变，包括MYC扩增，这是一种与激素逃逸相关的事件。有趣的是，我们发现两个克隆通过部署不同的进化路径获得AR基因扩增。总的来说，这些数据证明了肿瘤对治疗反应的演变时间框架，并为液体活检的多尺度分析提供了框架，以量化和监测个体患者的疾病演变。
Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.
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影响因子：
28.2
作者：
Miyamoto DT;Lee RJ;Stott SL;Ting DT;Wittner BS;Ulman M;Smas ME;Lord JB;Brannigan BW;Trautwein J;Bander NH;Wu CL;Sequist LV;Smith MR;Ramaswamy S;Toner M;Maheswaran S;Haber DA
通讯作者：
Haber DA
影响因子：
64.8
作者：
Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
通讯作者：
Wigler M
影响因子：
158.5
作者：
Cristofanilli, M;Budd, GT;Hayes, DF
通讯作者：
Hayes, DF
影响因子：
11.2
作者：
Heitzer, Ellen;Auer, Martina;Speicher, Michael R.
通讯作者：
Speicher, Michael R.
影响因子：
7
作者：
Navin, Nicholas;Krasnitz, Alexander;Wigler, Michael
通讯作者：
Wigler, Michael