Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.
Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
Cancer Res. 2021 Jul 1;81(13):3649-3663. doi: 10.1158/0008-5472.CAN-20-1799. Epub 2021 May 11.
Although intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. Although migration is typically considered to be associated with metastasis, when injected orthotopically , the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. Although both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential and that E-cadherin promotes metastasis in phenotypically sorted breast cancer cell subpopulations by enabling CTC clustering. SIGNIFICANCE: This study employs phenotypic cell sorting for migration to reveal a weakly migratory, highly metastatic breast cancer cell subpopulation regulated by E-cadherin, highlighting the dichotomy between cancer cell migration and metastasis.
虽然肿瘤内基因组异质性可能会阻碍癌症的研究和治疗，但人们对表型异质性的影响知之甚少。为了研究细胞迁移异质性在转移中的作用，我们根据迁移能力对转移性乳腺癌细胞进行了表型分选，将其分为两个亚群。虽然迁移通常被认为与转移有关，但当进行原位注射时，弱迁移亚群的转移明显多于高迁移亚群。为了研究这一观察结果背后的机制，我们在转移级联的每个阶段评估了这两个亚群，包括从原发性肿瘤扩散、在循环中存活、血管外渗和定植。尽管这两个亚群都成功地完成了每一个步骤，但弱迁移细胞在循环中以循环肿瘤细胞（CTC）簇的形式出现，这表明聚集是弱迁移细胞转移增加的一个潜在机制。RNA 测序显示，弱迁移亚群更上皮，高迁移亚群更间质。从弱迁移细胞中敲低 E-钙黏蛋白的表达可消除转移。相反，诱导高迁移细胞中 E-钙黏蛋白的表达会增加转移。临床患者数据和血液样本表明，CTC 聚集和 E-钙黏蛋白表达均与患者预后恶化相关。这项研究表明，去卷积表型异质性可以揭示转移性进展的基本见解。更具体地说，这些结果表明，迁移能力不一定与转移潜能相关，并且 E-钙黏蛋白通过允许 CTC 聚集来促进表型分选的乳腺癌细胞亚群的转移。意义：本研究采用迁移的表型细胞分选来揭示一个弱迁移、高转移性的乳腺癌细胞亚群，该亚群受 E-钙黏蛋白调控，突出了癌细胞迁移和转移之间的二分法。
