PO.TB09.02 · 肿瘤生物学
与淋巴结转移相关的前列腺癌克隆演进的空间分析
Spatial profiling of prostate cancer clonal evolution linked to nodal metastases
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌(PCa)进展为转移性疾病仍是一项关键的临床挑战，因此深入了解使某些亚克隆得以侵袭和扩散的因素至关重要。在我们此前通过从空间转录组数据推断拷贝数改变(CNA)来研究良性和恶性前列腺组织中基因组变异的研究基础上¹，本研究旨在追踪PCa亚克隆在前列腺内以及向引流淋巴结的空间演进轨迹，并识别转移转变相关微环境特征的改变。
为此，我们对来自10例个体的整个前列腺轴向切片及患者匹配的淋巴结转移灶进行了空间转录组学分析。采用标准空间转录组学(55μm)进行组织分析；从空间转录组数据中推断拷贝数改变(CNA)以识别不同的肿瘤亚克隆，并构建系统发育树以描述其演化关系。此外，采用高分辨率空间转录组学(2μm)技术，在两例选定患者中获得围绕特定亚克隆的紧邻肿瘤微环境(TME)的细胞水平视图。
对超过1,000,000个条形码区域的分析识别出许多不同的肿瘤亚克隆，使我们能够在空间上追踪其演化轨迹。我们观察到淋巴结内显著的亚克隆事件，包括多克隆定植，表明在原发疾病演化过程中存在多个起源事件。对紧邻TME的探索揭示了显著的细胞异质性，以及与抗原呈递和炎症通路相关基因的上调，这些主要集中在祖先肿瘤克隆附近，特别是在肿瘤边界处。通过聚焦于跨患者的转移克隆推断的CNA谱，我们识别出几个界定转移转变的共同特征。此外，我们能够在前列腺切除术前数月采集的匹配诊断活检中识别这些转移克隆，这提示了在初诊时识别潜在致死性疾病的可能性。
总之，我们的研究提供了PCa克隆演进和播散的详细空间图谱，将原发肿瘤与淋巴结转移相连接，并揭示了肿瘤克隆边界周围细胞组成和基因表达的改变。重要的是，它证实了淋巴结内的亚克隆事件、多克隆定植，以及在诊断时识别转移克隆的潜力，这对PCa的风险分层和治疗决策具有重要意义。
1. Erickson, A., He, M., Berglund, E. 等。良性和恶性组织中空间解析的克隆拷贝数改变。Nature 608, 360-367 (2022)。https://doi.org/10.1038/s41586-022-05023-2
查看英文原文 English abstract
The progression of prostate cancer (PCa) to metastatic disease remains a critical clinical challenge, making it essential to gain a detailed understanding of the factors that enable certain subclones to invade and spread. Building on our previous study, which examined genomic variations in benign and malignant prostate tissues by inferring copy number alterations (CNA) from spatial transcriptomics data 1 , this study aims to trace the spatial evolutionary trajectories of PCa subclones within the prostate and to draining lymph nodes and to identify alterations in associated microenvironments features of the metastatic transition.
To achieve this, we performed spatial transcriptomics on entire prostate axial disks and patient-matched lymph node metastases from 10 individuals. Standard spatial transcriptomics (55 µm) was used for tissue profiling; from the spatial transcriptomics data, copy number alterations (CNAs) were inferred to identify distinct tumor subclones, and phylogenetic trees constructed to describe their evolutionary relationships. Additionally, high-resolution spatial transcriptomics (2 µm) technology was employed to gain a cellular-level view of the immediate tumor-microenvironment (TME) surrounding specific subclones in two selected patients.
Analysis of over 1,000,000 barcoded regions identified many distinct tumor subclones, enabling us to trace their evolutionary trajectories spatially. We observed notable subclonal events within the lymph nodes, including polyclonal colonization, indicating multiple origin events during the evolution of the primary disease. Exploration of the immediate TME revealed significant cellular heterogeneity and upregulation of genes related to antigen presentation and inflammatory pathways concentrated near ancestral tumor clones, specifically at the tumor border. By focusing on the inferred CNA profiles of the metastasizing clone across patients, we identified several common features defining the metastatic transition. Additionally, we were able to identify these metastasizing clones in matched diagnostic biopsies taken several months before prostatectomy was performed, raising the possibility of identifying potentially lethal disease at presentation.
In summary, our study provides a detailed spatial map of PCa clonal evolution and dissemination, linking primary tumors to nodal metastases and revealing altered cell composition and gene expression around tumor clone borders. Importantly, it demonstrates subclonal events within lymph nodes, polyclonal colonization, and the potential to identify metastasizing clones at diagnosis, with implications for risk-stratification and treatment decisions in PCa.
1. Erickson, A., He, M., Berglund, E. et al. Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature 608 , 360-367 (2022). https://doi.org/10.1038/s41586-022-05023-2
利益披露 Disclosure
A. D. Lamb, None..
M. Beesley, None.