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

Bujamin H. Vokshi, Guillaume Davidson, Nassim Tawanaie Pour Sedehi, Alexandra Helleux, Marc Rippinger, Alexandre R. Haller, Justine Gantzer, Jonathan Thouvenin, Philippe Baltzinger, Rachida Bouarich, Valeria Manriquez, Sakina Zaidi, Priya Rao, Pavlos Msaouel, Xiaoping Su, Hervé Lang, Thibault Tricard, Véronique Lindner, Didier Surdez, Jean-Emmanuel Kurtz, Franck Bourdeaut, Nizar M. Tannir, Irwin Davidson () and Gabriel G. Malouf ()
Additional contact information
Bujamin H. Vokshi: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Guillaume Davidson: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Nassim Tawanaie Pour Sedehi: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Alexandra Helleux: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Marc Rippinger: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Alexandre R. Haller: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Justine Gantzer: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Jonathan Thouvenin: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Philippe Baltzinger: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Rachida Bouarich: INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre
Valeria Manriquez: INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre
Sakina Zaidi: INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre
Priya Rao: The University of Texas MD Anderson Cancer Center
Pavlos Msaouel: The University of Texas MD Anderson Cancer Center
Xiaoping Su: The University of Texas MD Anderson Cancer Center
Hervé Lang: CHRU Strasbourg, Strasbourg University
Thibault Tricard: CHRU Strasbourg, Strasbourg University
Véronique Lindner: CHRU Strasbourg, Strasbourg University
Didier Surdez: Balgrist University Hospital, University of Zurich
Jean-Emmanuel Kurtz: Institut de Cancérologie Strasbourg Europe
Franck Bourdeaut: INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, Institut Curie Research Centre
Nizar M. Tannir: The University of Texas MD Anderson Cancer Center
Irwin Davidson: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Gabriel G. Malouf: Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38472-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38472-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38472-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().