| Autor: |
Bouarich R, Manriquez, Xiaoping Su, Rippinger M, Sakina Zaidi, Didier Surdez, Justine Gantzer, Kurtz J, Vokshi Bh, Irwin Davidson, Haller Ar, Herve Lang, Gabriel G. Malouf, Pavlos Msaouel, Helleux A, Lindner, Philippe Baltzinger, Guillaume Davidson, Tricard T, Franck Bourdeaut, Nizar M. Tannir, Thouvenin J |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.09.29.462391 |
| Popis: |
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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/462391v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@3cb5c2org.highwire.dtl.DTLVardef@1c0fec2org.highwire.dtl.DTLVardef@195a2a4org.highwire.dtl.DTLVardef@e8d250_HPS_FORMAT_FIGEXP M_FIG C_FIG |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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