Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2024-06-10 DOI:10.1016/j.ccell.2024.05.011

Clémentine Sarkozy, Shaocheng Wu, Katsuyoshi Takata, Tomohiro Aoki, Susana B. Neriah, Katy Milne, Talia Goodyear, Celia Strong, Tashi Rastogi, Laura K. Hilton, Daniel Lai, Laurie H. Sehn, Pedro Farinha, Brad H. Nelson, Andrew Weng, Marco Marra, David W. Scott, Jeffrey W. Craig, Christian Steidl, Andrew Roth

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引用次数: 0

Abstract

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

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综合单细胞分析揭示了转化型滤泡淋巴瘤中恶性 B 细胞和肿瘤微环境的共同进化过程

滤泡性淋巴瘤（FL）在组织学上转变为侵袭性淋巴瘤与预后不良有关。这种演变的表型后果及其对肿瘤微环境（TME）的影响仍然未知。我们对 11 例转化前后配对的患者样本进行了单细胞全基因组测序（scWGS）和转录组测序（scWTS），并对未转化患者的其他样本进行了单细胞全基因组测序（scWGS）和转录组测序（scWTS）。我们的分析揭示了转化在单细胞分辨率上的进化动态，凸显了不断变化的TME景观，其中有一个新出现的免疫细胞衰竭特征，在一个调控生态系统中与不断变化的恶性B表型共同进化。整合 scWGS 和 scWTS 可识别克隆性肿瘤演变过程中上调的恶性细胞通路。利用多色免疫荧光，我们将这些发现转化为基于 TME 的转化生物标记物，随后在两个独立的预处理队列中进行了验证。总之，我们的研究结果提供了一个全面的视角，让人们了解恶性细胞在转化过程中基因组和表型的综合演变，以及恶性细胞与 TME 之间的串扰变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.