Smith Abigail O, Frantz William Tyler, Preval Kenley M, Edwards Yvonne J K, Ceol Craig J, Jonassen Julie A, Pazour Gregory J
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States of America.
Morningside Graduate School of Biological Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States of America.
PLoS Genet. 2024 Dec 12;20(12):e1011510. doi: 10.1371/journal.pgen.1011510. eCollection 2024 Dec.
Polycystic kidney disease (PKD) is an important cause of kidney failure, but treatment options are limited. While later stages of the disease have been extensively studied, mechanisms driving the initial conversion of kidney tubules into cysts are not understood. To identify genes with the potential to promote cyst initiation, we deleted polycystin-2 (Pkd2) in mice and surveyed transcriptional changes before and immediately after cysts developed. We identified 74 genes which we term cyst initiation candidates (CICs). To identify conserved changes with relevance to human disease we compared these murine CICs to single cell transcriptomic data derived from patients with PKD and from healthy controls. Tumor-associated calcium signal transducer 2 (Tacstd2) stood out as an epithelial-expressed gene with elevated levels early in cystic transformation that further increased with disease progression. Human tissue biopsies and organoids show that TACSTD2 protein is low in normal kidney cells but is elevated in cyst lining cells, making it an excellent candidate for mechanistic exploration of its role in cyst initiation. While TACSTD2 has not been studied in PKD, it has been studied in cancer where it is highly expressed in solid tumors while showing minimal expression in normal tissue. This property is being exploited by antibody drug conjugates that target TACSTD2 for the delivery of cytotoxic drugs. Our finding that Tacstd2/TACSTD2 is prevalent in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2-directed treatment for breast and urothelial cancer should be monitored for kidney effects.
多囊肾病（PKD）是肾衰竭的一个重要原因，但治疗选择有限。虽然该疾病的后期阶段已得到广泛研究，但驱动肾小管最初转化为囊肿的机制尚不清楚。为了鉴定具有促进囊肿起始潜力的基因，我们在小鼠中删除了多囊蛋白-2（Pkd2），并调查了囊肿形成之前和之后立即发生的转录变化。我们鉴定出74个基因，我们将其称为囊肿起始候选基因（CIC）。为了鉴定与人类疾病相关的保守变化，我们将这些小鼠CIC与来自PKD患者和健康对照的单细胞转录组数据进行了比较。肿瘤相关钙信号转导蛋白2（Tacstd2）作为一种上皮表达基因脱颖而出，在囊性转化早期水平升高，并随着疾病进展进一步增加。人体组织活检和类器官显示，TACSTD2蛋白在正常肾细胞中含量较低，但在囊肿内衬细胞中升高，这使其成为探究其在囊肿起始中作用机制的极佳候选基因。虽然尚未在PKD中对TACSTD2进行研究，但在癌症研究中，它在实体瘤中高度表达，而在正常组织中表达极少。针对TACSTD2的抗体药物偶联物利用这一特性来递送细胞毒性药物。我们发现Tacstd2/TACSTD2在囊肿中普遍存在，但在正常组织中不存在，这表明它应作为PKD药物开发的候选基因进行探索。更直接地说，我们的工作表明，接受针对TACSTD2的乳腺癌和尿路上皮癌治疗的PKD患者应监测肾脏影响。
