Nature Communications：多基因组谱系追踪预测癌症进化的转录、表观遗传和遗传决定因素-动脉网

Nature Communications：Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution

Nature 等信源发布 2024-09-01 21:47

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AbstractCancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population.

摘要癌症是一种高度异质性的疾病，表型不同的亚群共存，并可能导致不同的命运。遗传和表观遗传因素都可能驱动癌症的进化，但是对于这种过程是否以及如何在癌症克隆中预先编码知之甚少。使用单细胞多组谱系追踪和表型分析，我们研究了同一癌症人群中肿瘤起始或药物耐受性的预测特征。

Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories.

体内引发肿瘤起始的克隆在基线时显示两种不同的转录状态。值得注意的是，这些状态具有独特的DNA可及性特征，突出了肿瘤发生的表观遗传基础。耐药生态位也在很大程度上是预先编码的，但仅与肿瘤起始部分重叠，并沿着两个遗传和转录不同的轨迹进化。

Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes..

我们的研究强调了癌症进化的共存遗传，表观遗传和转录决定因素，揭示了预先编码的肿瘤表型的分子复杂性。。

IntroductionCancer adopts evolutionary pathways that sustain the disease. Aggressive tumour behaviours, such as the dissemination to distant organs, diminished susceptibility to treatment, and disease relapse, result from either selection or adaptation processes, possibly intertwined1. When a selective process occurs, the fate of a cancer clone is determined at the root of the evolutionary process.

引言癌症采用维持疾病的进化途径。侵袭性肿瘤行为，例如向远处器官的传播，对治疗的敏感性降低和疾病复发，可能是由选择或适应过程引起的，可能是相互交织的1。当发生选择性过程时，癌症克隆的命运取决于进化过程的根源。

In this case, the heterogeneity of tumour phenotypes can, at least in principle, be identified ahead of selection2. The pre-existence of aggressive phenotypes has been linked to the so-called cancer stem cell (CSC) theory3 and observed in leukaemia4,5 and solid tumours, such as colon6 and breast cancer7,8, as well as glioma9,10.

在这种情况下，至少原则上可以在选择之前确定肿瘤表型的异质性2。侵袭性表型的预先存在与所谓的癌症干细胞（CSC）理论3有关，并在白血病4,5和实体瘤如结肠癌6和乳腺癌7,8以及胶质瘤9,10中观察到。

According to such a model, tumour cells are not all equal, instead a stem-like cancer niche exists that is primed to sustain most of the aggressive phenotypes, such as tumour re-initiation, metastatic dissemination potential, and capacity to survive cytotoxic treatments11.Predicting cancer phenotypes requires linking the molecular state of a clone to its fate with high precision.

根据这样的模型，肿瘤细胞并不都是平等的，相反，存在一个干细胞样的癌症生态位，它可以维持大多数侵袭性表型，如肿瘤重新启动，转移性传播潜能和细胞毒性治疗的生存能力11。预测癌症表型需要将克隆的分子状态与其命运高度精确地联系起来。

Without a priori information, tumour phylogeny can be inferred from somatic mutations12,13,14,15; however, this approach is limited by the high sparsity of single-cell data. Single-cell lineage tracing consists in inserting barcodes in the genome of the cells with the aim of tracing their progeny16,17,18,19.

没有先验信息，可以从体细胞突变推断肿瘤系统发育12,13,14,15；然而，这种方法受到单细胞数据高度稀疏的限制。单细胞谱系追踪包括在细胞基因组中插入条形码，目的是追踪其后代16,17,18,19。

In cancer, this approach has been used to investigate clonality in metastases20, survival upon cytotoxic treatment21,22, as well as to dissect the clonal origin of the primary tumour and metastasis growth23,24,25,26, possibly in vivo27. However, these studies mainly focus on the evolutionary trajectories, rather than on the driving molecular features of pre-existing pheno.

在癌症中，这种方法已被用于研究转移的克隆性20，细胞毒性治疗后的存活率21,22，以及解剖原发肿瘤的克隆起源和转移生长23,24,25,26，可能在体内27。然而，这些研究主要集中在进化轨迹上，而不是先前存在的现象的驱动分子特征。

Data availability

数据可用性

The raw data generated in this study have been deposited in the ArrayExpress database under accession codes E-MTAB-13064, E-MTAB-13066 and E-MTAB-13896, in the GEO database under accession code GSE222596 and in the SRA database under accession code PRJNA922938. The processed data generated in this study have been deposited in Zenodo106 and are provided in the Supplementary Information/Source Data file.

本研究中产生的原始数据已以登录号E-MTAB-13064，E-MTAB-13066和E-MTAB-13896保存在ArrayExpress数据库中，以登录号GSE222596保存在GEO数据库中，以登录号PRJNA922938保存在SRA数据库中。本研究中产生的处理数据已保存在Zenodo106中，并在补充信息/源数据文件中提供。

The raw data used in this study are available in the GEO database under accession GSE161529. The processed data used in this study are available at https://doi.org/10.1016/j.ccell.2021.05.005 (https://ars.els-cdn.com/content/image/1-s2.0-S1535610821002713-mmc6.xlsx), https://doi.org/10.1038/s41586-023-06130-4 (https://www.dropbox.com/scl/fi/22xtcdh0z7bnn5g5ugz33/meta_programs_2023-07-13.xlsx?rlkey=2e7d718s46zybiyvjuptm67n4&dl=1) and https://doi.org/10.1016/j.ccell.2020.06.006 (https://www.cell.com/cms/10.1016/j.ccell.2020.06.006/attachment/f5a9ca73-3dc5-413d-99b0-24d348abf2f3/mmc4.xls). Source data are provided with this paper..

本研究中使用的原始数据可在GEO数据库中以登录号GSE161529获得。本研究中使用的处理数据可在https://doi.org/10.1016/j.ccell.2021.05.005（笑声）(https://ars.els-cdn.com/content/image/1-s2.0-S1535610821002713-mmc6.xlsx)，https://doi.org/10.1038/s41586-023-06130-4（笑声）(https://www.dropbox.com/scl/fi/22xtcdh0z7bnn5g5ugz33/meta_programs_2023-07-13.xlsx?rlkey=2e7d718s46zybiyvjuptm67n4&dl=1)和https://doi.org/10.1016/j.ccell.2020.06.006（笑声）(https://www.cell.com/cms/10.1016/j.ccell.2020.06.006/attachment/f5a9ca73-3dc5-413d-99b0-24d348abf2f3/mmc4.xls)。。。

Code availability

代码可用性

The code used to reproduce the analysis reported in this study is available on github at https://github.com/nicassiolab/GBC_SUM159PT_paper and https://github.com/nicassiolab/GBC_SUM159PT_paper_figures. All codes have been deposited in Zenodo107,108.

用于重现本研究报告的分析的代码可在github上获得https://github.com/nicassiolab/GBC_SUM159PT_paper和https://github.com/nicassiolab/GBC_SUM159PT_paper_figures.所有代码都保存在Zenodo107108中。

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Nadalin, F. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution—processed data- https://doi.org/10.5281/zenodo.10912157 (2023).Nadalin, F. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution—reproducibility https://doi.org/10.5281/zenodo.10979191 (2023).Nadalin, F.

Nadalin，F。多组谱系追踪预测了癌症进化处理数据的转录，表观遗传和遗传决定因素-https://doi.org/10.5281/zenodo.10912157（2023年）。Nadalin，F。多组谱系追踪预测癌症进化可重复性的转录，表观遗传和遗传决定因素https://doi.org/10.5281/zenodo.10979191（2023年）。纳达林，F。

Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution—source code- https://doi.org/10.5281/zenodo.10979121 (2023).Download referencesAcknowledgementsThis work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to F.

多组谱系追踪预测癌症进化源代码的转录，表观遗传和遗传决定因素-https://doi.org/10.5281/zenodo.10979121（2023年）。下载参考文献致谢这项工作得到了意大利协会（Associazione Italiana per la Ricerca sul Cancro）（AIRC）对F的资助。

Nicassio (IG18774 and IG22851), from the Fondazione Cariplo to F. Nicassio (2015-0590) and M.J.M. (2016-0615), and from “National Center for Gene Therapy and Drugs based on RNA Technology” (CN00000041) supported by European Union—NextGenerationEU PNRR MUR—M4C2 to F. Nicassio; and “Roche per la ricerca 2018” to M.J.M.

Nicassio（IG18774和IG22851），从Fondazione Cariplo到F.Nicassio（2015-0590）和M.J.M.（2016-0615），以及“基于RNA技术的国家基因治疗和药物中心”（CN00000041），由欧盟下一代PNRR MUR-M4C2支持F.Nicassio；和“Roche per la ricerca 2018”给M.J.M。

F. Nadalin was supported by a REBIT-POD fellowship. B.G. was supported by a FIRC-AIRC fellowship for Italy (22438). J.C.M. and I.P. acknowledge funding from EMBL member states. M.P.P. is a PhD student within the European School of Molecular Medicine (SEMM). Figures 1a, b; 2a, h; 3a; 4a; 5c; 6d, e; 7a and Supplementary Figs. 1a, 5a were created with BioRender.com and released under a Creative Commons Attribution-NonCommercial-NoDerivs (CC-BY-NC-ND) 4.0 International license.

F、 Nadalin得到了REBIT-POD奖学金的支持。B、 G.得到了FIRC-AIRC意大利奖学金（22438）的支持。J、 C.M.和I.P.感谢EMBL成员国的资助。M、 P.P.是欧洲分子医学院（SEMM）的博士生。图1a，b；；3a；4a；5c；6d，e；7a和补充图1a，5a是由BioRender.com创建的，并根据知识共享署名非商业性NoDerivs（CC-BY-NC-ND）4.0国际许可证发布。

We thank Chiara Tordonato for help with mice experiments; Leah Rosen and Magdalena Strauss for input on barcode analysis; Pier Giuseppe Pelicci, Niccolò Roda and Valentina Gambino for help with the Perturb-seq lentiviral infection. We acknowledge support by the technological units at t.

我们感谢Chiara Tordonato对小鼠实验的帮助；Leah Rosen和Magdalena Strauss为条形码分析提供信息；Pier Giuseppe Pelicci，NiccolòRoda和Valentina Gambino为扰动-seq慢病毒感染提供帮助。我们感谢t的技术部门的支持。

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PubMed Google ScholarContributionsF. Nadalin: conceptualisation, methodology, investigation, writing—original draft preparation. M.J.M.: conceptualisation, investigation, writing—review and editing. M.P.P.: investigation, writing—review & editing. P.F.: investigation, writing—review & editing.

PubMed谷歌学术贡献。纳达林：概念化，方法论，调查，写作原稿准备。M、 J.M.：概念化，调查，写作评论和编辑。M、 P.P.：调查，写作评论和编辑。P、 F.：调查、写作、评论和编辑。

S.P.: formal analysis. M.C.: investigation. P.B.: investigation. C.R.: resources. B.G.: resources. I.P.: supervision, writing—review & editing. J.C.M.: supervision, writing—review & editing. F. Nicassio: conceptualisation, funding acquisition, supervision, writing—original draft preparation.Corresponding authorsCorrespondence to.

S、 P：形式分析。M、 C.：调查。P、 B.：调查。C、 R.：资源。B、 G.：资源。一、 P：监督，写作审查和编辑。J、 C.M.：监督，写作审查和编辑。F、尼卡西奥：概念化，资金获取，监督，撰写原始草案。。

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J.C.M. has been an employee of Genentech since September 2022. The remaining authors declare no competing interests.

J、自2022年9月以来，C.M.一直是基因泰克的员工。其余作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleNadalin, F., Marzi, M.J., Pirra Piscazzi, M. et al. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.

转载和许可本文引用本文Nadalin，F.，Marzi，M.J.，Pirra Piscazzi，M。等人。多组谱系追踪预测癌症进化的转录，表观遗传和遗传决定因素。

Nat Commun 15, 7609 (2024). https://doi.org/10.1038/s41467-024-51424-4Download citationReceived: 10 August 2023Accepted: 05 August 2024Published: 01 September 2024DOI: https://doi.org/10.1038/s41467-024-51424-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157609（2024）。https://doi.org/10.1038/s41467-024-51424-4Download引文接收日期：2023年8月10日接收日期：2024年8月5日发布日期：2024年9月1日OI：https://doi.org/10.1038/s41467-024-51424-4Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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