Department of Anatomy and.
Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA.
J Clin Invest. 2024 Sep 3;134(17):e164227. doi: 10.1172/JCI164227.
Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.
转移是癌症相关死亡的主要原因。目前尚不清楚肿瘤内异质性（ITH）如何促进转移，以及转移细胞如何适应远处组织环境。由于患者材料获取有限，以及缺乏适当重现 ITH 的实验模型，这些适应的研究受到了挑战。为了研究转移细胞的适应性以及 ITH 对转移的贡献，我们分析了来自乳腺癌患者来源异种移植模型的配对原发肿瘤和转移瘤的单细胞转录组。我们发现原发肿瘤和转移细胞之间存在明显的转录差异。原发肿瘤上调了几个代谢基因，而微转移瘤中上调了运动途径基因，进展过程中上调了应激反应信号。此外，我们确定了与增加转移潜力相关并与患者预后相关的原发肿瘤基因特征。免疫调节控制途径在转移性差的原发肿瘤中富集，而上皮-间充质转化相关的基因在高转移性肿瘤中上调。我们发现 ITH 主要由上皮-间充质可塑性（EMP）主导，EMP 呈现出一种动态连续体，具有特定基因，如 CRYAB 和 S100A2 的中间 EMP 细胞状态。中间 EMP 特征的高表达与患者预后较差相关。我们的研究结果确定抑制中间 EMP 细胞状态可能是阻止转移的潜在治疗靶点。
