Mechanism of early dissemination and metastasis in Her2(+) mammary cancer.
Mechanism of early dissemination and metastasis in Her2(+) mammary cancer.
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DOI：
10.1038/nature20609
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发表时间：
2016-12-22
期刊：
影响因子：
64.8
通讯作者：
Aguirre-Ghiso JA
中科院分区：
文献类型：
--
作者：
Harper KL;Sosa MS;Entenberg D;Hosseini H;Cheung JF;Nobre R;Avivar-Valderas A;Nagi C;Girnius N;Davis RJ;Farias EF;Condeelis J;Klein CA;Aguirre-Ghiso JA
转移是癌症相关死亡的主要原因；转移性病变由可保持休眠状态的播散性癌细胞 (DCC) 发展而来。转移起始细胞被认为起源于进展性侵袭性肿瘤中存在的亚群。然而，在乳腺癌转移出现之前在患者中检测到的 DCC 比原发肿瘤或转移患者的 DCC 含有更少的遗传异常。这些发现以及胰腺癌和黑色素瘤模型中的发现表明，传播可能发生在肿瘤进化的早期阶段。然而，早期播散性癌细胞（eDCC）完成所有转移步骤的机制尚不清楚。在这里，我们表明，在小鼠的早期病变中，在检测到任何明显的原发性肿瘤块之前，存在 Her2+p-p38lop-Atf2loTwist1hiE-cadlo 早期癌细胞亚群，该细胞具有侵袭性并且可以扩散到靶器官。早期病变的活体成像和类器官研究表明，Her2+ eDCC 前体局部侵入、渗入并滞留在靶器官中。 Her2+ eDCC 激活了 Wnt 依赖性上皮间质转化 (EMT) 样传播程序，但没有完全丧失上皮表型，而 Her2 或 Wnt 抑制可逆转这种情况。值得注意的是，尽管大多数 eDCC 是 Twist1hiE-cadlo 且处于休眠状态，但它们最终启动了转移。我们的工作确定了一种早期传播机制，其中 Her2 异常激活一个类似于乳腺导管分支的程序，该程序生成能够在休眠期后形成转移的 eDCC。
Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours. However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2+p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC precursors invaded locally, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent epithelial–mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1hiE-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.