Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY Genome Medicine Pub Date : 2024-01-29 DOI:10.1186/s13073-023-01272-6
Shenglin Mei, Adele M Alchahin, Ioanna Tsea, Youmna Kfoury, Taghreed Hirz, Nathan Elias Jeffries, Ting Zhao, Yanxin Xu, Hanyu Zhang, Hirak Sarkar, Shulin Wu, Alexander O Subtelny, John Inge Johnsen, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A Randolph, David T Scadden, Douglas M Dahl, John Shin, Peter V Kharchenko, Philip J Saylor, David B Sykes, Ninib Baryawno
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Abstract

Background: Despite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards identification of therapeutic targets.

Methods: We collected fresh patient samples and performed single-cell transcriptomic profiling of solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), and liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow from patients undergoing hip replacement surgery (Benign). In addition, we incorporated single-cell data from primary ccRCC tumors (ccRCC Primary) for comparative analysis.

Results: The bone marrow of metastatic patients is immune-suppressive, featuring increased, exhausted CD8 + cytotoxic T cells, T regulatory cells, and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival and also markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption.

Conclusions: These results provide a comprehensive analysis of the bone marrow niche in the setting of human metastatic cancer and highlight potential therapeutic targets for both cell populations and communication channels.

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对透明细胞肾细胞癌原发肿瘤和骨转移病灶中免疫细胞和基质细胞重塑的单细胞分析。
背景:尽管治疗手段不断进步,但癌症一旦转移到骨骼,就会成为一种高发病率和致命性疾病。三分之一的晚期透明细胞肾细胞癌(ccRCC)患者在确诊时已出现骨转移。然而,人类骨转移龛(包括免疫和基质微环境)尚未得到很好的界定,这阻碍了确定治疗靶点的进展:我们收集了新鲜的患者样本,并对实体转移组织(Bone Met)、脊髓受压椎体水平的液态骨髓(Involved)、远离肿瘤部位但在手术区域内的不同椎体的液态骨髓(Distal)以及接受髋关节置换手术患者的骨髓(Benign)进行了单细胞转录组分析。此外,我们还纳入了原发性ccRCC肿瘤(ccRCC Primary)的单细胞数据进行比较分析:结果:转移性患者的骨髓具有免疫抑制作用,其特点是CD8 +细胞毒性T细胞、T调节细胞和肿瘤相关巨噬细胞(TAM)增多且衰竭,在转移性病灶中具有不同的转录状态。来自肿瘤样本的骨髓基质显示了肿瘤相关间充质基质细胞群(TA-MSC),它似乎支持上皮向间充质转化(EMT)、骨重塑和癌症相关成纤维细胞(CAFs)表型。这种基质亚群与无进展生存期和总生存期差有关,还通过失调骨细胞中的RANK/RANKL/OPG信号活性显著上调骨重塑,最终导致骨吸收:这些结果提供了对人类转移性癌症骨髓生态位的全面分析,并突出了细胞群和通讯渠道的潜在治疗靶点。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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