Petra Jagust, Aoibhin M Powell, Mihaela Ola, Louise Watson, Ana de Pablos-Aragoneses, Pedro García-Gómez, Ramón Fallon, Fiona Bane, Mona Heiland, Gareth Morris, Brenton Cavanagh, Jason McGrath, Daniela Ottaviani, Aisling Hegarty, Sinéad Cocchiglia, Kieron J Sweeney, Stephen MacNally, Francesca M Brett, Jane Cryan, Alan Beausang, Patrick Morris, Manuel Valiente, Arnold D K Hill, Damir Varešlija, Leonie S Young
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引用次数: 0
摘要
背景:乳腺癌脑转移的发生率越来越高,因此有必要更好地了解相关机制,以便进行有效治疗。乳腺癌脑转移灶与原发肿瘤有明显差异,激酶增加,同时类固醇信号丢失。在这项研究中,我们探讨了激酶受体RET在促进乳腺癌脑转移中的作用,并为靶向该受体提供了理论依据:方法:在一组原发性和脑转移性肿瘤患者中鉴定了 RET 的表达。方法:研究人员对原发性和脑转移瘤患者组群中 RET 的表达进行了表征,并在患者来源的脑转移瘤外植体和体内模型、类器官模型和脑组织型培养物中使用药理抑制和基因沉默法对 RET 的功能进行了评估。利用 RNA 测序发现了与脑转移相关的新型 RET 作用机制:结果:在雌激素受体阳性乳腺癌中观察到,RET在脑转移瘤中的富集具有统计学意义,它在促进癌细胞在脑中的粘附、存活和生长方面发挥作用。在体内,RET 的过表达增强了患者衍生模型的脑转移能力。在机理层面上,研究发现RET的过表达会增强参与细胞粘附的基因程序的激活,这需要表皮生长因子受体(EGFR)的合作,以提供一种促进脑转移的表型:我们的研究结果首次说明了 RET 在调节乳腺癌脑转移的定植和生长中的作用,并为在乳腺癌脑转移患者的治疗策略中使用 RET 抑制剂提供了数据支持。
RET overexpression leads to increased brain metastatic competency in luminal breast cancer.
Background: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor.
Methods: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action.
Results: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype.
Conclusion: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.
期刊介绍:
The Journal of the National Cancer Institute is a reputable publication that undergoes a peer-review process. It is available in both print (ISSN: 0027-8874) and online (ISSN: 1460-2105) formats, with 12 issues released annually. The journal's primary aim is to disseminate innovative and important discoveries in the field of cancer research, with specific emphasis on clinical, epidemiologic, behavioral, and health outcomes studies. Authors are encouraged to submit reviews, minireviews, and commentaries. The journal ensures that submitted manuscripts undergo a rigorous and expedited review to publish scientifically and medically significant findings in a timely manner.