Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
Department of Molecular and Medical Genetics, Oregon Health & Science University Portland, Portland, OR, 97239-3098, USA.
Nat Commun. 2020 Nov 16;11(1):5799. doi: 10.1038/s41467-020-19584-1.
The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit-and-run" commensal interactions.
肿瘤细胞功能异质性和串扰的程度和重要性尚未得到充分理解。在这里，我们描述了从患者来源的卵巢透明细胞癌模型中产生克隆群体的过程，该模型在小鼠腹腔内移植后会形成恶性腹水和实体腹膜肿瘤。这些克隆群体被工程改造为分泌型 Gaussia 荧光素，以监测肿瘤生长动态，并标记独特的 DNA 条码，以在肿瘤进展过程中多克隆混合物中跟踪其命运。只有一个克隆 CL31 生长旺盛，仅产生恶性腹水。然而，多克隆混合物形成大的实体腹膜转移瘤，几乎完全由 CL31 组成，这表明短暂的合作性克隆间相互作用足以促进 CL31 的转移。CL31 独特地携带 ERBB2 扩增，其在克隆混合物中的获得性转移活性依赖于短暂暴露于 amphiregulin，而 amphiregulin 仅由非致瘤克隆分泌。amphiregulin 增强了 CL31 间皮清除，这是转移的先决条件。这些发现表明，短暂的、表面上无害的肿瘤亚群可以通过“打一枪换一个地方”的共生相互作用促进转移。
