Determinants of Liver Metastasis

项目摘要/摘要。 非酒精性脂肪性肝病可使肝脏允许发生肝转移。服用雄激素的患者 治疗前列腺癌的信号转导抑制剂，如苯扎鲁胺，也有类似的生物学特性 肝脏的变化。患者血脂的这些全身性变化与肝脏损伤有关 可量化地加速肝组织的生物老化。前列腺癌细胞获得基因 能够作为转移性利基在肝脏中存活的适应。我们发现苯扎鲁胺暴露于 谷氨酰胺依赖促进BMP配体在前列腺癌上皮细胞中的表达 举止。苯扎鲁胺还增加了SLC1A5的表达，SLC1A5是一种能够调节肿瘤的谷氨酰胺转运蛋白 成长。无谷氨酰胺培养的前列腺癌上皮细胞BMP配体水平显著降低 与谷氨酰胺、谷氨酸或苯扎鲁胺处理的细胞相比。谷氨酰胺抑制被发现阻断了 SLC1A5在与前列腺癌相关成纤维细胞共培养的前列腺上皮细胞中的表达这个 利用这些抑制剂，谷氨酰胺转运到上皮细胞的机制被充分阻断，并且 成纤维细胞特异性基因也受到影响。前列腺癌组织中WNT3a的表达和谷氨酰胺分泌 苯扎鲁胺后相关成纤维细胞增多，谷氨酰胺抑制后相关成纤维细胞减少。基于这些 新发现，我们测试了谷氨酰胺抑制是否对前列腺癌微环境有效，其中 前列腺癌上皮细胞与癌相关成纤维细胞共培养。我们发现苯扎鲁胺 前列腺上皮细胞神经内分泌分化增加，当共培养时被 谷氨酰胺抑制剂单独或与苯扎鲁胺联合使用。苯扎鲁胺对甲基化的潜在作用 在使用苯扎鲁胺处理的前列腺上皮细胞中观察到与生物老化相关的标志物 TET2启动子在其下游靶标TBX2上的浓集增加；谷氨酰胺抑制作用减弱 启动子浓缩。我们假设高脂饮食引起的肝脏生物老化会影响肝脏。 允许前列腺癌转移的微环境。在目标1中，我们将定义肝脏的表观遗传学变化 发生是使用苯扎鲁胺抑制雄激素信号的结果。我们将确定多高脂肪的饮食 在无肿瘤的环境中影响肝脏的甲基化模式。在目标2中，我们将确定 高脂饮食或苯扎鲁胺治疗原发肿瘤后引起的肝脏生物老化 发生。我们发现前列腺癌上皮细胞中甲基胞嘧啶双加氧酶TET2的表达发生突变。 使用苯扎鲁胺或谷氨酰胺治疗会增加患癌症的风险。我们将探索雄激素-TET2的串扰 在前列腺癌上皮细胞中作为一种适应性促进肝转移。高脂肪饮食的机制 而肝脏老化对前列腺癌肝脏转移的影响将被研究。

Project Summary/Abstract. Non-alcoholic fatty liver disease can make the liver permissive to liver metastasis. Patients taking an androgen signaling inhibitor, such as enzalutamide for the treatment of prostate cancer can experience similar biologic changes to the liver. These systemic changes in the patient lipid profile are associated with liver injury can result in a quantifiable acceleration of biologic aging of the liver tissue. Prostate cancer cells acquire genetic adaptations that enable survival in the liver as a metastatic niche. We found that enzalutamide exposure promoted expression of BMP ligands in prostate cancer epithelial cells in a glutamine signaling-dependent manner. Enzalutamide also increased expression of SLC1A5, a glutamine transporter able to regulate tumor growth. Prostate cancer epithelial cells grown without glutamine had significantly lower levels of BMP ligands compared to cells treated with glutamine, glutamate or enzalutamide. Glutamine inhibition was found to block expression of SLC1A5 in prostate epithelia co-cultured with prostate cancer-associated fibroblasts. The mechanism of transporting glutamine into the epithelial cells was sufficiently blocked using these inhibitors, and fibroblast-specific genes were also affected. Wnt3a expression and glutamine secretion in prostate cancer- associated fibroblasts increased after enzalutamide but decreased with glutamine inhibition. Based on these novel findings, we tested if glutamine inhibition could be effective on the prostate tumor microenvironment, where prostate cancer epithelia and cancer-associated fibroblasts were co-cultured. We found that enzalutamide increased neuroendocrine differentiation in prostate epithelia, abrogated when co-cultures were treated with glutamine inhibitor alone or in combination with enzalutamide. The potential role of enzalutamide on methylation markers associated with biologic aging was observed where prostate epithelia treated with enzalutamide had increased promoter enrichment of TET2 on its downstream target TBX2; glutamine inhibition decreased promoter enrichment. We hypothesize that biologic aging of the liver induced by high fat diet impacts the hepatic microenvironment to permit prostate metastasis. In Aim 1, we will define epigenetic changes in the liver that occur as a result of androgen signaling inhibition using enzalutamide. We will determine how high fat diet influences methylation patterns in the liver in a tumor-free environment. In Aim 2, we will identify the role of biologic aging in the liver induced by high fat diet or enzalutamide treatment after primary tumor expansion occurs. We found that prostate cancer epithelial expression of TET2, a methylcytosine dioxygenase mutated in cancers, is increased with enzalutamide or glutamine treatments. We will explore the androgen-TET2 crosstalk in prostate cancer epithelia as an adaptation promoting liver metastasis. The mechanism by which high fat diet and liver aging contribute to prostate cancer metastasis to the liver will be studied.