Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities

Abstract

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities.

Renal Medullary Carcinomas Harbor a Distinct Methylation Phenotype and Display Aberrant Methylation of Genes Related to Early Nephrogenesis

“…It has previously been shown that the expression of both genes is upregulated in RMCs [ 5 ], which corroborates our results. Additionally, our findings are in line with the study by Vokshi et al, which showed clusters of cells harboring an EMT signature in single cell transcriptome analyses of a RMC patient sample as well as an enrichment of EMT and hypoxia in two independently generated RMC cell lines [ 13 ]. Although RMCs and ES show similarities in global methylation, as seen in hierarchical clustering ( Figure 1 B), the methylation of genes involved in nephrogenesis showed clear differences.…”

“…The hypertonicity and hypoxia within the renal medulla and the location of SMARCB1 at 22q11.2, a known hotspot for de novo deletions and translocations that occur under hypoxic stress, are important factors in the progression of RMCs [ 12 ]. A recent study by Vokshi et al [ 13 ] showed an activation of ferroptosis resistance pathways in RMC cells, which helps to link the RMC oncogenic process to its association with the sickle cell trait. The increased iron concentration in the extracellular space caused by sickled red blood cells (RBCs) leads to selective pressure for ferroptosis resistant cells, which seem to be cells harboring a SMARCB1 loss [ 13 ].…”

“…A recent study by Vokshi et al [ 13 ] showed an activation of ferroptosis resistance pathways in RMC cells, which helps to link the RMC oncogenic process to its association with the sickle cell trait. The increased iron concentration in the extracellular space caused by sickled red blood cells (RBCs) leads to selective pressure for ferroptosis resistant cells, which seem to be cells harboring a SMARCB1 loss [ 13 ].…”

Systematic Review of Treatment of Metastatic Non-Clear Cell Renal Cell Carcinoma

“…This study found that potential therapies that affect the DNA damage pathway, such as PARP inhibitors, including olaparib and niraparib, ATR inhibitors, and WEE1 inhibitors could all present promising therapies for this nccRCC subtype [90]. Single-cell transcriptomics has also identified potential therapeutic targets in medullary RCC, including novel targetable immune checkpoint receptors TIGIT and CD96, contrasting with low PD1 and CTLA4 expression [91]. Another study evaluated somatic and germline mutations from 116 patients with metastatic nccRCC.…”