Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Nature. 2019 Mar;567(7749):540-544. doi: 10.1038/s41586-019-1019-4. Epub 2019 Mar 13.
Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy. Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade, remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.
肿瘤内或肿瘤间（称为患者内肿瘤异质性）在疾病进展过程中发生的多样性是治疗的严重障碍。转移是癌症的致命标志，而定植的机制（转移级联中最复杂的步骤）仍然定义不明确。更清楚地了解肿瘤内异质性和转移的基础的细胞和分子过程对于个性化癌症治疗的成功至关重要。在这里，我们使用在小鼠来源的异种移植模型中对肿瘤和匹配转移进行的转录谱分析，显示了癌症部位特异性表型和远处转移中糖皮质激素受体活性的增加。糖皮质激素受体介导应激激素的作用，以及这些激素的合成衍生物的作用，这些衍生物在临床上广泛用作抗炎和免疫抑制药物。我们表明，乳腺癌进展过程中应激激素的增加导致糖皮质激素受体在远处转移部位的激活、定植增加和存活率降低。我们的转录组学、蛋白质组学和磷酸化蛋白质组学研究表明，糖皮质激素受体参与转移中的多个过程的激活以及激酶 ROR1 的表达增加，这两者都与存活率降低相关。ROR1 的消融减少了临床前模型中的转移生长并延长了存活。我们的结果表明，糖皮质激素受体的激活增加了异质性和转移，这表明在使用糖皮质激素治疗已经发生癌症相关并发症的乳腺癌患者时需要谨慎。
