Amlexanox

A team of Cleveland Clinic researchers has discovered that our own white blood cells play a pivotal role in helping breast cancer metastasize to the brain. The PNAS article from the laboratory of Peiwen Chen, PhD, describes how breast cancer cells that travel to the brain shape the surrounding tissue to form a favorable tumor microenvironment, promoting metastasis and tumor growth. “There’s a real unmet need for patients whose breast cancer has spread to the brain because treatment options are extremely limited, and outcomes are usually poor,” says study lead author Fatima Khan, PhD, a postdoctoral fellow in Dr. Chen’s lab. “There’s been some evidence that the immune system in our body helps shape metastasis, so I wanted to know which immune cells are truly driving tumor growth and survival and how they were doing it.” Dr. Khan first analyzed publicly available cancer databases to look for key signaling pathway differences between primary breast tumors and brain metastatic breast tumors. She then used computational analysis, laboratory bench work and preclinical models to understand how tumors could develop brain metastasis. In doing so, she unraveled a complicated communication network between healthy and cancerous cells in our brains that drive breast cancer brain metastasis (BCBM). “These breast cancer cells aren’t just showing up in the brain and setting up shop in hostile territory,” Dr. Khan says. “They’re tricking the infiltrating healthy cells in our brains into making the environment welcoming and hospitable. It's less like a violent takeover and more like a manipulative conversation.” Here’s what Dr. Khan discovered happens when breast cancer metastasizes to our brains: Breast cancer cells that reach the brain secrete molecules called MMP1 into the surrounding tissue. These secreted molecules reach brain-infiltrating white blood cells, which start making an immune-related molecule called TBK1. TBK1 “activates” the immune cells and tells them to work for the cancer metastasis. The pro-tumor white blood cells are called tumor-associated macrophages (TAMs). Activated TAMs then secrete molecules called GM-CSF into the brain tissue. GM-CSF goes back to the cancer cells and tells them how to migrate through, invade into and set up tumor residence in the brain, fueling metastatic outgrowth. With each step the Chen Lab uncovered in the communication network between BCBM cells and TAMs in the brain, new potential drug targets emerged. Each target represented a point where the metastatic process could be interrupted. Blocking TBK1 in preclinical models proved especially powerful. It halted tumor growth, reversed metastasis and significantly extended survival. These results were seen with lab-only compounds and with Amlexanox, an FDA-approved drug that also inhibits TBK1 to treat canker sores. “If a drug is already approved for something else, we know a lot about its safety, so it’s much quicker and easier to move it into clinical trials for new indications compared to a brand-new drug,” Dr. Khan says. “Right now, we’re doing more testing with TBK1 inhibitors, including combinations with standard treatments. We hope to move into clinical trials soon.”

撰文丨王聪编辑丨王多鱼排版丨水成文朊蛋白（Prion Protein，PrP）存在两种形式——正确折叠的 PrPC 和错误折叠的 PrPSC，PrPC 主要参与神经系统发育、记忆形成等生物学过程，而 PrPSC 则会导致疯牛病、克雅氏病等朊病毒病。PrPC 主要在神经系统中表达，但在肾功能不全患者的血液和尿液中也有检测到。然而，PrPC 在肾病发展中的作用尚未得到探索。2025 年 4 月 16 日，南方医科大学南方医院肾病中心聂静团队与天津医科大学陈宇鹏团队合作，在 Science Translational Medicine 期刊发表了题为：Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis 的研究论文，该论文还被选为当期封面论文。该研究发现，肾脏 PrPC 蛋白水平在慢性肾病（CKD）患者及小鼠模型中均显著升高，该蛋白可通过相分离机制激活 TBK1-IRF3 信号轴，促进肾脏纤维进展。TBK1 抑制剂 Amlexanox 能够有效减缓疾病的发展，可作为肾脏纤维化的潜在治疗药物。定位细胞型朊蛋白：封面图片展示了单侧输尿管梗阻的小鼠近端肾小管上皮细胞（绿色）内的细胞型朊蛋白（PrPC，红色），蓝色为细胞核。该研究发现，慢性肾病患者近端肾小管中 PrPC 表达上调，进而通过相分离形成凝聚物，激活促炎信号级联反应，引发近端肾小管上皮细胞和成纤维细胞的促纤维化反应，从而揭示了 PrPC 促进慢性肾病的机制。慢性肾脏病（CKD）是全球性重要公共卫生问题，有着较高的发病率和死亡率。肾脏纤维化是 CKD 进展至终末期肾衰竭的共同途径，其主要特征包括细胞外基质异常沉积，肾小管萎缩，间质慢性炎症等。尽管对肾脏纤维化的发病及机制已有广泛研究，临床上仍缺乏有效的治疗靶点及药物。在这项最新研究中，研究团队发现，慢性肾病（CKD）患者肾活检中的纤维化肾损伤区域中 PrPC 表达上调，主要在近端肾小管上皮细胞（PTEC）中。此外，在慢性肾病患者中，肾脏中 PrPC 的表达与肾衰竭的严重程度以及估算肾小球滤过率的下降呈正相关。在小鼠中，特异性敲除肾小管中的 PrPC 可减轻由单侧输尿管梗阻（UUO）或单侧缺血再灌注损伤（UIRI）所诱导的肾纤维化。从机制上来说，PrPC 通过 TGFβ1-Smad3 信号通路而上调。PrPC 通过其液-液相分离（LLPS）的能力激活了 TBK1-IRF3 信号通路，从而促进了 PTEC 和成纤维细胞的促纤维化反应。在肾纤维化发生之前（在单侧输尿管梗阻和缺血再灌注损伤模型中）或发生之后（在腺嘌呤和马兜铃酸诱导的慢性肾病模型中）用，使用美国 FDA 批准的 TBK1 抑制剂氨来呫诺（Amlexanox）治疗小鼠，可减轻肾纤维化的恶化和肾功能的下降。总的来说，这项研究揭示了 PrPC 的相分离在肾纤维化中的作用机制，并支持进一步研究 PrPC-TBK1-IRF3 信号轴作为慢性肾病（CKD）的潜在治疗靶点。南方医科大学南方医院肾病中心聂静教授、天津医科大学表观遗传学协同创新中心陈宇鹏教授为论文通讯作者。南方医科大学南方医院博士研究生龙潭潭、马圆媛，天津医科大学基础医学院博士研究生陆玉妹、宋艳东为该论文第一作者。论文链接：https://www.science.org/doi/10.1126/scitranslmed.adj9095设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味