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

Autor: Vokshi BH; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Davidson G; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Tawanaie Pour Sedehi N; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Helleux A; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Rippinger M; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Haller AR; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Gantzer J; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France.; Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, 67200, Strasbourg, France., Thouvenin J; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France.; Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, 67200, Strasbourg, France., Baltzinger P; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France., Bouarich R; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre, 75005, Paris, France., Manriquez V; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre, 75005, Paris, France., Zaidi S; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre, 75005, Paris, France., Rao P; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Msaouel P; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Su X; Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Lang H; Department of Urology, CHRU Strasbourg, Strasbourg University, 67000, Strasbourg, France., Tricard T; Department of Urology, CHRU Strasbourg, Strasbourg University, 67000, Strasbourg, France., Lindner V; Department of Pathology, CHRU Strasbourg, Strasbourg University, 67200, Strasbourg, France., Surdez D; Balgrist University Hospital, University of Zurich, Zurich, Switzerland.; INSERM, U830, Pediatric Translational Research, PSL Research University, SIREDO Oncology Center, Institut Curie, Paris, France., Kurtz JE; Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, 67200, Strasbourg, France., Bourdeaut F; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre, 75005, Paris, France., Tannir NM; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Davidson I; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France. irwin@igbmc.fr.; 'Équipe Labellisée' Ligue National contre le Cancer, Paris, France. irwin@igbmc.fr., Malouf GG; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France. maloufg@igbmc.fr.; Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, 67200, Strasbourg, France. maloufg@igbmc.fr.; 'Équipe Labellisée' Ligue National contre le Cancer, Paris, France. maloufg@igbmc.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 26; Vol. 14 (1), pp. 3034. Date of Electronic Publication: 2023 May 26.
DOI: 10.1038/s41467-023-38472-y
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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