SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance

Abstract

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into three RMC cell states along an epithelial-mesenchymal gradient by loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

Update on Selected High-grade Renal Cell Carcinomas of the Kidney: FH-deficient, ALK-rearranged, and Medullary Carcinomas

“…Despite sharing SMARCB1 biallelic alterations, RMC shows a distinct DNA methylation phenotype from malignant rhabdoid tumor and epithelioid sarcoma, and certain genes regulating nephrogenesis (such as Forkhead Box I1 (FOXI1) may display aberrant methylation and gene expression 55 . Interestingly, applying single-cell technology in a small number of RMC cases, a couple of recent studies identify tumor cell populations with gene expression signatures suggestive of a cell-of-origin from the thick ascending limb of the loop of Henle 56,57 . Overall, recent mechanistic studies suggest that loss of SMARCB1 promotes cell survival and transformation in response to extreme hypoxia or the high extracellular iron levels in the medulla of sickle cell trait patients 56–58 …”

“…Interestingly, applying single-cell technology in a small number of RMC cases, a couple of recent studies identify tumor cell populations with gene expression signatures suggestive of a cell-of-origin from the thick ascending limb of the loop of Henle 56,57 . Overall, recent mechanistic studies suggest that loss of SMARCB1 promotes cell survival and transformation in response to extreme hypoxia or the high extracellular iron levels in the medulla of sickle cell trait patients 56–58 …”