Insights from single cell and bulk RNA sequencing: increased NOTCH signaling is correlated with oncogenic transformation of juxtaglomerular cells to juxtaglomerular cell tumors

Abstract

Renin-expressing juxtaglomerular cells in the kidney are the cell of origin for rare juxtaglomerular cell tumors, and affected patients often experience prolonged diagnostic odysseys as they present with relatively nonspecific symptoms related to secondary hypertension. While NOTCH1-3 gene rearrangements are the predominant molecular finding in similar (non-renin producing) “myopericytic” cell-derived glomus tumors that occur at renal and non-renal sites, such alterations have been reported in only isolated cases of juxtaglomerular cell tumors. As pathogenic mechanisms contributing to the oncogenic transformation of juxtaglomerular cells to renin-producing tumors are poorly defined due to their extreme rarity, we compared single cell RNA sequencing data for (non-neoplastic) juxtaglomerular cells to bulk whole transcriptomic data for a series of six fusion-negative juxtaglomerular cell tumors. Unsupervised clustering revealed substantial alterations in gene expression in juxtaglomerular cell tumors compared to their cell of origin, including significant over-expression of markers that are diagnostically relevant (renin/GATA3), and other (upregulated) markers of interest including CD34, NOTCH2/3, PDGFRB, JAG1, and NTRK3. Finally, the majority of juxtaglomerular cell tumors showed increased NOTCH pathway signaling. These findings help better define the pathologic basis of oncogenic transformation of juxtaglomerular cells to renin-expressing tumors and may be informative regarding therapeutic options in unresectable or rare cases of metastatic juxtaglomerular cell tumors.