Metastatic tumor cells in bone marrow differ from paired neuroblastoma tumor and contain subsets with therapy-resistant characteristics

Caroline Hochheuser, Arjan Boltjes, Kaylee M Keller, Simon Tol, Marieke van de Mheen, Caroline Pita Barros, Zeinab van Gestel-Fadaie, André B.P. van Kuilenburg, Sander van Hooff, Carlijn Voermans, Jan J. Molenaar, Godelieve A.M. Tytgat, Ilse Timmerman
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Abstract

Bone marrow (BM) is a common site for solid tumor metastasis, often causing poor outcome. Here, we define the characteristics of BM-disseminated tumor cells (DTCs) using neuroblastoma as a model. We combined single-cell RNA-sequencing (scRNA-seq) and cell-surface protein analysis using 7 paired BM and primary tumor (PT) samples and found that DTCs contain a higher percentage of cycling cells and higher expression of neurodevelopmental genes compared to corresponding PT cells. In 6 patients, the copy number variation profile differed between PT cells and DTCs, indicating spatial heterogeneity. Within the BM, we detected dormant DTCs with potentially reduced chemosensitivity; this population contained cells expressing low levels of the immunotherapeutic antigen GD2 and increased NGFR expression. In conclusion, we characterized DTCs that are particularly challenging to target, offering new avenues for developing therapeutic strategies designed to target all subpopulations within the highly complex metastatic site, thereby preventing the development of drug-resistant clones.
骨髓中的转移性肿瘤细胞与配对的神经母细胞瘤肿瘤不同,包含具有抗药性特征的亚群
骨髓(BM)是实体瘤转移的常见部位,通常导致不良预后。在这里,我们以神经母细胞瘤为模型,确定了骨髓播散肿瘤细胞(DTCs)的特征。我们利用7个配对的BM和原发肿瘤(PT)样本,结合单细胞RNA测序(scRNA-seq)和细胞表面蛋白分析,发现与相应的PT细胞相比,DTCs含有更高的循环细胞比例和更高的神经发育基因表达。在6例患者中,PT细胞和DTC细胞的拷贝数变异情况不同,表明存在空间异质性。在 BM 中,我们发现了休眠的 DTC,其化疗敏感性可能会降低;该群体中的细胞表达低水平的免疫治疗抗原 GD2,并且 NGFR 表达增加。总之,我们鉴定了特别具有挑战性的 DTCs,为开发治疗策略提供了新的途径,这些策略旨在针对高度复杂的转移部位内的所有亚群,从而防止耐药克隆的发展。
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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