Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.
USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California.
Cancer Discov. 2020 Jan;10(1):86-103. doi: 10.1158/2159-8290.CD-19-0384. Epub 2019 Oct 10.
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that -cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain..
血行转移是由原发性或转移性肿瘤脱落到血液循环中的一小部分循环肿瘤细胞（CTC）引发的。因此，CTC 为破译引发转移的细胞亚群及其分子特性提供了独特的患者活检资源。然而，一个关键问题是，是否可以从患者中获得并扩增 CTC，以在动物模型中重现人类转移性疾病。在这里，我们证明了从乳腺癌患者中建立的 CTC 系能够在小鼠中产生转移，其模式重现了大多数来自相应患者的主要器官。对转移变体的全基因组测序分析鉴定出 Sema4D 是肿瘤细胞通过血脑屏障迁移的调节剂，MYC 是播散的肿瘤细胞适应激活的脑微环境的关键调节剂。这些数据为 CTC 作为特定部位转移的预后因素的有前途的作用提供了直接的实验证据。意义：人们对了解脑转移的病理生理学有浓厚的兴趣。在直接的转移性趋化性分析中，我们证明了来自 4 名乳腺癌患者的培养 CTC 显示出器官趋向性，揭示了允许一小部分 CTC 进入和在大脑中生长的分子特征。
