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Single-Cell-Derived Primary Rectal Carcinoma Cell Lines Reflect Intratumor Heterogeneity Associated with Treatment Response.
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2020-07-01 , DOI: 10.1158/1078-0432.ccr-19-1984
Rüdiger Braun 1 , Lena Anthuber 1 , Daniela Hirsch 1 , Darawalee Wangsa 1 , Justin Lack 2, 3 , Nicole E McNeil 1 , Kerstin Heselmeyer-Haddad 1 , Irianna Torres 1 , Danny Wangsa 1 , Markus A Brown 1 , Anthony Tubbs 4 , Noam Auslander 5 , E Michael Gertz 5 , Philip R Brauer 1 , Margaret C Cam 6 , Dan L Sackett 7 , Jens K Habermann 8 , Andre Nussenzweig 4 , Eytan Ruppin 5 , Zhongqiu Zhang 9 , Daniel W Rosenberg 10 , Thomas Ried 1
Affiliation  

Purpose: The standard treatment of patients with locally advanced rectal cancer consists of preoperative chemoradiotherapy (CRT) followed by surgery. However, the response of individual tumors to CRT is extremely diverse, presenting a clinical dilemma. This broad variability in treatment response is likely attributable to intratumor heterogeneity (ITH). Experimental Design: We addressed the impact of ITH on response to CRT by establishing single-cell–derived cell lines (SCDCL) from a treatment-naïve rectal cancer biopsy after xenografting. Results: Individual SCDCLs derived from the same tumor responded profoundly different to CRT in vitro . Clonal reconstruction of the tumor and derived cell lines based on whole-exome sequencing revealed nine separate clusters with distinct proportions in the SCDCLs. Missense mutations in SV2A and ZWINT were clonal in the resistant SCDCL, but not detected in the sensitive SCDCL. Single-cell genetic analysis by multiplex FISH revealed the expansion of a clone with a loss of PIK3CA in the resistant SCDCL. Gene expression profiling by tRNA-sequencing identified the activation of the Wnt, Akt, and Hedgehog signaling pathways in the resistant SCDCLs. Wnt pathway activation in the resistant SCDCLs was confirmed using a reporter assay. Conclusions: Our model system of patient-derived SCDCLs provides evidence for the critical role of ITH for treatment response in patients with rectal cancer and shows that distinct genetic aberration profiles are associated with treatment response. We identified specific pathways as the molecular basis of treatment response of individual clones, which could be targeted in resistant subclones of a heterogenous tumor.

中文翻译:

单细胞衍生的原发性直肠癌细胞系反映了与治疗反应相关的肿瘤内异质性。

目的:局部晚期直肠癌患者的标准治疗包括术前放化疗 (CRT) 和手术。然而,个体肿瘤对 CRT 的反应极其多样,呈现出临床困境。治疗反应的这种广泛变异可能归因于肿瘤内异质性(ITH)。实验设计:我们通过从异种移植后未经治疗的直肠癌活检中建立单细胞衍生细胞系 (SCDCL) 来解决 ITH 对 CRT 反应的影响。结果:来自同一肿瘤的个体 SCDCL 对体外 CRT 的反应截然不同。基于全外显子组测序的肿瘤和衍生细胞系的克隆重建揭示了 SCDCL 中具有不同比例的九个独立簇。SV2A 和 ZWINT 中的错义突变在抗性 SCDCL 中是克隆性的,但在敏感 SCDCL 中未检测到。通过多重 FISH 进行的单细胞遗传分析揭示了在抗性 SCDCL 中丢失 PIK3CA 的克隆的扩增。通过 tRNA 测序进行的基因表达谱分析确定了抗性 SCDCL 中 Wnt、Akt 和 Hedgehog 信号通路的激活。使用报告基因检测证实了抗性 SCDCL 中 Wnt 通路的激活。结论:我们的源自患者的 SCDCL 模型系统为 ITH 在直肠癌患者治疗反应中的关键作用提供了证据,并表明不同的遗传畸变谱与治疗反应相关。我们确定了特定途径作为单个克隆治疗反应的分子基础,
更新日期:2020-07-01
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