Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA.
Cell Rep. 2019 Sep 10;28(11):2837-2850.e5. doi: 10.1016/j.celrep.2019.08.029.
Cellular heterogeneity is frequently observed in cancer, but the biological significance of heterogeneous tumor clones is not well defined. Using multicolor reporters and CRISPR-Cas9 barcoding, we trace clonal dynamics in a mouse model of sarcoma. We show that primary tumor growth is associated with a reduction in clonal heterogeneity. Local recurrence of tumors following surgery or radiation therapy is driven by multiple clones. In contrast, advanced metastasis to the lungs is driven by clonal selection of a single metastatic clone (MC). Using RNA sequencing (RNA-seq) and in vivo assays, we identify candidate suppressors of metastasis, namely, Rasd1, Reck, and Aldh1a2. These genes are downregulated in MCs of the primary tumors prior to the formation of metastases. Overexpression of these suppressors of metastasis impair the ability of sarcoma cells to colonize the lungs. Overall, this study reveals clonal dynamics during each step of tumor progression, from initiation to growth, recurrence, and distant metastasis.
肿瘤中经常观察到细胞异质性，但异质性肿瘤克隆的生物学意义尚未明确。本研究使用多色报告基因和 CRISPR-Cas9 条形码，追踪了肉瘤小鼠模型中的克隆动态。研究结果表明，原发性肿瘤的生长与克隆异质性的降低有关。手术或放射治疗后肿瘤的局部复发是由多个克隆驱动的。相比之下，晚期肺转移则是由单个转移性克隆（MC）的克隆选择驱动的。通过 RNA 测序（RNA-seq）和体内实验，研究人员鉴定出了候选转移抑制基因，即 Rasd1、Reck 和 Aldh1a2。这些基因在转移前的原发性肿瘤 MC 中下调。过表达这些转移抑制基因会损害肉瘤细胞在肺部定植的能力。总的来说，这项研究揭示了肿瘤进展的每个阶段的克隆动态，包括起始、生长、复发和远处转移。
