Xiao Jerry, Sharma Utsav, Arab Abolfazl, Miglani Sohit, Bhalla Sonakshi, Suguru Shravanthy, Suter Robert, Mukherji Reetu, Lippman Marc E, Pohlmann Paula R, Zeck Jay C, Marshall John L, Weinberg Benjamin A, He Aiwu Ruth, Noel Marcus S, Schlegel Richard, Goodarzi Hani, Agarwal Seema
School of Medicine, Georgetown University, Washington, DC 20057, USA.
Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA.
Cancers (Basel). 2023 Mar 17;15(6):1831. doi: 10.3390/cancers15061831.
Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (, , , , and ). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 () as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.
循环肿瘤细胞（CTCs）是一群癌细胞，代表着转移结节的种子，是研究转移的一个有前景的模型系统。然而，体外扩增患者来源的CTCs具有挑战性，且依赖于收集大量极其罕见的CTCs。在此，我们报告了一种联合CTCs和培养的CTCs来源异种移植（CDX）平台的开发，用于扩增和研究来自转移性结肠癌、肺癌和胰腺癌患者的CTCs。扩增后的CTCs产生了一群高度侵袭性的细胞，可用于在CDX中常规且可靠地建立原发性肿瘤和转移病灶。对所得CTCs模型的差异基因分析强调了NF-κB、上皮-间质转化（EMT）和转化生长因子β（TGFβ）信号作为参与转移的泛癌信号通路的作用。此外，通过一个前瞻性的五基因特征（、、、和）鉴定出了转移性CTCs。对CDX模型和转移灶的全外显子测序进一步确定了组成型光形态发生蛋白1（）中的突变是转移的一个潜在驱动因素。这些发现说明了联合患者来源CTCs模型的实用性，并让我们初步看到了CTCs在识别癌症转移驱动因素方面的前景。
