英国威康桑格研究所Lucy R. Yates，瑞典斯德哥尔摩大学Mats Nilsson和欧洲生物信息学研究所Moritz Gerstung共同合作，近期取得重要工作进展。他们研究通过空间基因组学描绘癌症克隆的结构、性质和演变。相关论文2022年11月9日在线发表于《自然》杂志上。

研究人员开发了一个工作流程，可以生成整个肿瘤切片中遗传亚克隆组成的详细定量图谱。这为研究克隆生长模式、组织学特征、显微解剖和微环境组成提供了基础。该方法基于全基因组测序，其次是高度多重的碱基特异性原位测序、单细胞解析转录组学和连接这些层的专用算法。将碱基特异性原位测序工作流程应用于两种多灶原发性乳腺癌的八个组织切片，揭示了复杂的亚克隆生长模式，并通过显微解剖进行了验证。

在原位导管癌的病例中，多克隆肿瘤扩张发生在宏观尺度上，但在微观解剖结构中分离。在导管原位癌、浸润性癌和淋巴结转移的各个阶段，亚克隆区域显示出不同的转录和组织学特征以及细胞微环境。这些结果证明，空间基因组学能辅助破译癌症演化和微环境生态学中的相关机制。

据介绍，癌症的基因组测序常常显示在同一个肿瘤中存在不同亚克隆的嵌合体。尽管这些被认为是根据体细胞演化的原理产生的，但确切的空间生长模式和潜在的机制仍然难以捉摸。

附：英文原文

Title: Spatial genomics maps the structure, nature and evolution of cancer clones

Author: Lomakin, Artem, Svedlund, Jessica, Strell, Carina, Gataric, Milana, Shmatko, Artem, Rukhovich, Gleb, Park, Jun Sung, Ju, Young Seok, Dentro, Stefan, Kleshchevnikov, Vitalii, Vaskivskyi, Vasyl, Li, Tong, Bayraktar, Omer Ali, Pinder, Sarah, Richardson, Andrea L., Santagata, Sandro, Campbell, Peter J., Russnes, Hege, Gerstung, Moritz, Nilsson, Mats, Yates, Lucy R.

Issue&Volume: 2022-11-09

Abstract: Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1,2,3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

DOI: 10.1038/s41586-022-05425-2

Source: https://www.nature.com/articles/s41586-022-05425-2