测序技术的最新进展使肿瘤的分子研究得以深入,即使在单细胞水平。测序工作揭示了肿瘤细胞之间以前未被重视的异质性,这被认为是肿瘤发展的驱动力,并促进复发,转移,和抗药性。在目前的研究中,专注于早期可手术的非小细胞肺癌,我们使用小鼠患者源性异种移植(PDX)模型中的肿瘤生长作为快速的肿瘤进化过程来研究在小鼠中生长的肿瘤细胞的分子特征,以及影响接枝效率的参数。我们发现,与腺癌相比,鳞状细胞癌的移植效率更高。高级阶段,患者年龄和原发肿瘤大小与移植呈正相关.此外,我们从患者外周血中分离并表征了循环肿瘤细胞(CTC),发现表达上皮-间质(EMT)标志物的CTC的存在与移植潜力相关.有趣的是,PDX肿瘤的外显子组测序确定了DNA修复和基因组完整性基因中的遗传改变,这些基因在人类主要对应物中代表性不足.总之,通过产生NSCLC的PDX生物样本库,我们确定了影响小鼠生长的肿瘤的临床和分子特性。
Recent advances in sequencing technologies have allowed the in-depth molecular
study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current
study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients\' peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.