Nat Commu:结直肠癌近端淋巴结转移,由近到远?

2020-07-02 北京大学BIOPIC 北京大学BIOPIC

Nature Communications发表了北京大学生物医学前沿创新中心(BIOPIC)、生命科学学院白凡课题组的研究论文:Mapping the spreading routes of lymp

Nature Communications发表了北京大学生物医学前沿创新中心(BIOPIC)、生命科学学院白凡课题组的研究论文:Mapping the spreading routes of lymphatic metastases in human colorectal cancer(人类结直肠癌向淋巴系统转移的路径研究)。

推荐:参与#结直肠癌#话题

据WHO最新统计,结直肠癌是全球范围内发病率排名第三、致死率排名第二的癌种。原发性结直肠癌向近端淋巴系统及远端器官的转移是导致病人死亡的重要原因,然而远端器官转移的发生是否依赖于近端淋巴转移的形成是个颇受争议的问题,并且近端淋巴结的转移路径因缺乏有效的研究方法而未被揭示。

在本篇工作中,研究者严格筛选入组研究对象,全面精细取样,创新生物信息分析方法,将癌灶克隆组成进行解析,重构结直肠癌在时间、空间尺度的转移历史与路径。首先,研究者对入组的10个结直肠癌病例的原位病灶、肝脏转移灶进行多点取样,确保样本对于癌灶的代表性;对淋巴结转移灶全面阳筛,并按照其物理位置分为三站,即旁系(Paracolic)、中间(Intermediate)、中央(Central)淋巴结病灶,采用显微切割的方式提取肿瘤组织进行研究(图1)。

图1: 病人入组(a)及取样策略(b,c)示意图

接着,对样本进行高深度外显子组测序后,采用多种生物信息学方法高精度解析癌灶的克隆占比,利用鸽巢原理重构样本的克隆组成,构建克隆进化树,进而判断结直肠癌病人内克隆的发展及转移的历史,最终确定出稳定的、最大概率的肿瘤转移网络(图2)。

图2: 还原克隆组成(a)、克隆发展历史(b), 绘制肿瘤转移路径(c,d)

研究者发现在入组的病人中,已知的结直肠癌驱动突变(driver alterations) ,例如APC、KRAS、TP53突变等,大多发生在早期,存在于所有的癌细胞中。在所有的转移事件中,单克隆转移(monoclonal seeding)和多克隆转移(multiclonal seeding)方式分别占比26.2% 和73.8%,多克隆转移是结直肠癌发生转移的主要形式。通过对结直肠癌病人转移路径的还原,研究者发现37.7%的转移事件并不直接来自于原发灶的播散,而是来自转移灶的再转移播散(Metastases-to-metastases)。值得注意的是,不同淋巴结病灶的再转移能力有很大的差异,本研究在5个病例中发现了拥有高转移潜能的淋巴结转移灶。非常有趣的是,淋巴结转移不是依照简单的由近及远的顺序传播,而是存在着大量跨站“跳跃”转移的现象。对于远端肝脏转移来说,它既可以起源于原发病灶,也可以来自淋巴结转移灶亦或肝脏上已经存在的转移灶;在病例Patient_9中,两个肝转病灶分别来自原位播种与淋巴结转移灶的二次转移(图3),这说明结直肠癌远端转移的来源不能一概而论。本工作创新利用生物信息学方法,首次在时间和空间尺度上精细绘制了结直肠癌病人的转移图谱,为解决结直肠癌转移的相关重要问题提出了直接解答。

 

图3: 结直肠癌病人淋巴结转移(a)、远端肝脏转移(b)的路径还原及3种转移模式(c,d,e)

北京大学BIOPIC、生命科学学院博士生张冲,北京协和医学院中国医学科学院肿瘤医院博士生张林、徐田磊、俞亮,北京大学第一医院肿瘤转化研究中心助理研究员薛瑞栋为共同第一作者,国家癌症中心、中国医学科学院肿瘤医学张海增教授与北京大学BIOPIC、生命科学学院白凡研究员为通讯作者。

原始出处:

Zhang C, et al. Mapping the spreading routes of lymphatic metastases in human colorectal cancer.Nat Commun. 2020. PMID: 32332722 

白凡研究员

白凡,北京大学生物医学前沿创新中心、北京大学生命科学学院研究员,国家自然科学基金委优秀青年基金获得者。

1981年出生,2003年本科毕业于北京大学物理系,2008年获英国牛津大学生物物理博士学位,2008-2011年间先后在牛津大学、日本大阪大学从事博士后研究工作。长期从事进行细菌鞭毛分子马达、细菌趋化性和蛋白质输出机制的研究,于《自然》、《科学》等世界著名学术刊物发表多篇高水平论文。2011年全职回国后,白凡实验室致力于将先进的单细胞基因测序 技术应用于重大医学疾病问题的研究。在世界范围第一个报道单个循环肿瘤细胞的全基因组测序结果(PNAS,2013; Genome Research,2017; CCR,2019),获得广泛关注。通过使用微量细胞测序技术,深入研究了肝癌的各种肝内转移病灶,揭示出肝癌转移广泛的异质性(Gastroenterology, 2016; Cancer Cell, 2019)。结合单细菌荧光成像和高通量基因测序技术,深入探究了细菌耐药性产生的分子机制(Molecular Cell, 2016; Molecular Cell, 2019;获得Nature重点评述)。

    白凡实验室将综合利用单分子荧光显微成像技术、单细胞基因测序技术,研究与医学临床直接相关的前沿课题,包括:(1) 单细胞基因测序技术应用于癌症病人外周血循环肿瘤细胞研究,探索癌症转移的分子生物学机制及无创癌症诊断、预后判断、疗 效评价的临床方法;(2)大样本基因测序研究中国人群高发癌症的基因突变特征,发掘引起癌症表型转化、转移的关键驱动事件;(3)研究细菌行为、致病性,抗生素杀菌原理和细菌抗药、耐药的分子机制

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    2020-11-29 liye789132251
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    2020-07-04 sodoo
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    2020-07-04 hittouch
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    2020-07-02 student08989_52692172

    直接给予科研与临床新的思路🤔🤔

    0

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    2020-07-02 mswert122

    #结直肠癌#存在淋巴结跳跃转移,第一次听到

    0

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