Abstract Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicatin…

Abstract Background There are currently no proven therapies for metastatic or unresectable Chromophobe renal cell carcinoma (ChRCC). Ferroptosis is an iron-dependent form of cell death characterized by the peroxidation of membrane polyunsaturated fatty acids, leading to membrane damage and cell death. Glutathione, a potent cellular antioxidant, counters lipid peroxidation to prevent ferroptosis. Both reduced and oxidized glutathione are markedly elevated in ChRCC (PNAS, 2018). We have previously discovered that Ch…

Abstract While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in…

Abstract Background ChRCC is a rare form of kidney cancer and presents with a poor prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. While previous studies suggested that ChRCC originates from intercalated cells of the kidney, its exact cellular origin has not been clearly defined. We therefore investigated the cellular origin of ChRCC and renal oncocytic neoplasms at single-cell resolution. Methods ChRCC, renal oncocytoma (RO) and low-grade onco…

Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels …