Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.
Vokshi, B. H.; Davidson, G.; Helleux, A.; Rippinger, M.; Haller, A. R.; Gantzer, J.; Baltzinger, P.; Thouvenin, J.; Bouarich, R.; Manriquez, V.; Zaidi, S.; Msaouel, P.; Su, X.; Lang, H.; Tricard, T.; Lindner, V.; Surdez, D.; Kurtz, J.-E.; Bourdeaut, F.; Tannir, N. M.; Davidson, I.; Malouf, G. G.
Show 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. 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@152fa6eorg.highwire.dtl.DTLVardef@b76f50org.highwire.dtl.DTLVardef@ed1382org.highwire.dtl.DTLVardef@9be54f_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer 96%
- GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome. 96%
- IFNgamma-dependent remodelling of the myeloid landscape underlies control of IFNgamma-insensitive tumours 96%
Similar papers in this journal
- Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment 96%
- Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response 96%
- Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube 95%
Similar papers in this journal
- Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme 96%
- Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness 96%
- An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma 96%
Similar papers in this journal
- ROR1 plays a critical role in pancreatic tumor-initiating cells with a partial EMT signature. 95%
- An RNA-binding switch drives ribosome biogenesis and tumorigenesis downstream of RAS oncogene 94%
- Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.