Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

中文翻译：

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靶向治疗后微小残留病的细胞休眠

乳腺癌死亡率主要是由于肿瘤复发，肿瘤复发可能发生在长达数十年的临床缓解期之后。虽然临床潜伏期被认为反映了残留肿瘤细胞持续处于休眠状态的能力，但由于对这些细胞的生物学知之甚少，这一假设仍未得到证实。因此，确定残留肿瘤细胞的特性是一个基本目标，对于预防复发和改善癌症结果具有重要的临床意义。为了识别残留肿瘤细胞的保守特征，我们使用可诱导转基因小鼠模型来模拟 HER2/neu 和 Wnt1 驱动的肿瘤发生的微小残留病，该模型概括了人类乳腺癌进展的主要特征，以及接受靶向治疗的人类乳腺癌细胞异种移植物。荧光激活细胞分选用于从原发性肿瘤、癌基因阻断后的残留病灶和复发性肿瘤中分离肿瘤细胞，以分析基因表达特征并评估肿瘤起始细胞特性。我们证明，尽管有足够的血管化和缺乏适应性免疫，但在局部和远处部位幸存下来的致癌途径抑制的残留肿瘤细胞仍处于细胞休眠状态，并保留重新进入细胞周期并引起复发的能力。延长潜伏期后的肿瘤。与原发性或复发性肿瘤细胞相比，休眠残留肿瘤细胞具有独特的特征，这些特征在由不同癌基因驱动的人类乳腺癌小鼠模型中是保守的，并且表达与乳腺癌患者和类似患者的无复发生存密切相关的基因特征。与由微环境诱导休眠的肿瘤细胞相比。尽管 HER2/neu 和 Wnt1 模型中残留的肿瘤细胞都富集了与肿瘤起始细胞相关的表型特征，但有限稀释实验表明，残留的肿瘤细胞并未富集能够产生原发肿瘤的细胞，而是富集了能够产生原发肿瘤的细胞。能够产生复发性肿瘤的细胞，表明原发性肿瘤发生的肿瘤起始群体可能与治疗后引起复发的细胞不同。靶向治疗后幸存的残留癌细胞存在于局部和远处血管良好、促纤维增生的微环境中。这些细胞处于细胞休眠状态，与原发性或复发性肿瘤细胞几乎没有相似之处，但与微环境线索诱导休眠的细胞有相似之处。我们的观察表明，休眠可能是对靶向治疗的保守反应，与抑制的致癌途径或原发肿瘤的特性无关，局部和远处部位休眠的机制可能是相关的，