The role of the lung microenvironment in regulating metastatic colonisation by breast cancer

肺微环境在调节乳腺癌转移定植中的作用

• 批准号: 2454345
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2454345
• 关键词: role; lung; microenvironment; regulating; metastatic

The metastatic spread of breast cancer cells and their colonisation of important organs such as the lungs is the cause of death in 95% of breast cancer. Symptomatic lung metastases are also associated with poorer quality of life (increased morbidity) in breast cancer patients. We recently studied the bone metastatic microenvironment (Eyre et al., Nature Communications, in press, see above) and discovered cytokines and other secreted factors determine the interactions between metastatic breast cancer cells and the bone microenvironment. These factors are very important for the colonisation and tumour outgrowth at the metastatic site. In the current proposed project, we intend to apply the same paradigm to the lung microenvironment using the following objectives:1. To determine and quantitate important factors secreted by the lung microenvironment that stimulate breast cancer colony-forming activity.2. To use human breast cancer patient-derived xenograft (PDX) tumour models in immune-deficient mice to determine if the same factors are important in vivo and to quantify their expression.3. To test inhibitors of, and/or genetically delete these pathways in PDX models to prevent lung metastases.Briefly, we will establish cultures of lung epithelial cells and whole tissues from which the secreted factors will be extracted and tested on patient-derived breast cancer cells to determine whether they stimulate stem cell activity using the mammosphere colony assay established in our lab (Shaw et al., JMGBN, 2012). The secreted factors will be identified using cytokine arrays and RNAseq, as previously established for bone metastases, and the candidates will be tested individually and in combination for their stimulatory activity. The importance of these signalling pathways, in vivo, will be corroborated using PDX tumours established in our lab to undergo spontaneous lung metastasis (Eyre et al., JMGBN, 2016; Byrne et al., Nature Reviews Cancer, 2017). We will upregulate (gene overexpression) or delete (shRNA/CRISPR) genes in relevant pathways to discover their effect on the lung metastatic process in the in vivo microenvironment. Finally, we will use available small molecule or biological (antibody) inhibitor drugs to test preclinically for their efficacy in preventing secondary breast cancer in the lungs.The outcome will be the discovery of new important pathways involved in lung metastasis of breast cancer by using human tissue and tumours. These pathways may be targetable by existing drugs or novel drugs in development and be translatable to the clinic, via clinical drug development, to improve the therapeutic options for breast cancer patients at risk of secondary breast cancer.

乳腺癌细胞的转移扩散及其在肺等重要器官上的定植是95%乳腺癌患者死亡的原因。在乳腺癌患者中，有症状的肺转移也与较差的生活质量（发病率增加）相关。我们最近研究了骨转移微环境（Eyre et al., Nature Communications, in press，见上文），发现细胞因子和其他分泌因子决定了转移性乳腺癌细胞与骨微环境之间的相互作用。这些因素对于肿瘤在转移部位的定植和生长非常重要。在目前提出的项目中，我们打算将相同的范式应用于肺微环境，实现以下目标：确定和定量肺微环境分泌的刺激乳腺癌集落形成活动的重要因子。在免疫缺陷小鼠中使用人乳腺癌患者来源的异种移植（PDX）肿瘤模型来确定相同的因素在体内是否重要并量化它们的表达。在PDX模型中测试这些通路的抑制剂和/或基因删除以预防肺转移。简而言之，我们将建立肺上皮细胞和整个组织的培养物，从中提取分泌因子，并使用我们实验室建立的乳腺球集落试验在患者来源的乳腺癌细胞上进行测试，以确定它们是否刺激干细胞活性（Shaw等人，JMGBN, 2012）。分泌因子将使用细胞因子阵列和RNAseq进行鉴定，就像之前为骨转移建立的那样，候选因子将单独或联合测试其刺激活性。这些信号通路在体内的重要性将通过我们实验室建立的自发肺转移的PDX肿瘤得到证实（Eyre等人，JMGBN, 2016； Byrne等人，Nature Reviews Cancer, 2017）。我们将在相关通路上调（基因过表达）或删除（shRNA/CRISPR）基因，以发现其在体内微环境中对肺转移过程的影响。最后，我们将使用现有的小分子或生物（抗体）抑制剂药物对其预防肺部继发性乳腺癌的疗效进行临床前测试。结果将是通过使用人体组织和肿瘤发现涉及乳腺癌肺转移的新的重要途径。这些途径可能被现有药物或正在开发的新药靶向，并可通过临床药物开发转化为临床，以改善有继发性乳腺癌风险的乳腺癌患者的治疗选择。