Fiche publication
Date publication
mai 2023
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIDSON Irwin
,
Pr KURTZ Jean-Emmanuel
,
Pr LANG Hervé
,
Dr LINDNER Véronique
,
Pr MALOUF Gabriel
,
Dr TRICARD Thibault
,
Dr GANTZER Justine
,
Dr BALTZINGER Philippe
Tous les auteurs :
Vokshi BH, Davidson G, Tawanaie Pour Sedehi N, Helleux A, Rippinger M, Haller AR, Gantzer J, Thouvenin J, Baltzinger P, Bouarich R, Manriquez V, Zaidi S, Rao P, Msaouel P, Su X, Lang H, Tricard T, Lindner V, Surdez D, Kurtz JE, Bourdeaut F, Tannir NM, Davidson I, Malouf GG
Lien Pubmed
Résumé
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 an epithelial-mesenchymal gradient of RMC cells associated with 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.
Mots clés
Humans, Kidney Neoplasms, pathology, Sickle Cell Trait, Carcinoma, Medullary, metabolism, Ferroptosis, Carcinoma, Renal Cell, pathology, SMARCB1 Protein, genetics, Repressor Proteins, Homeodomain Proteins
Référence
Nat Commun. 2023 05 26;14(1):3034
