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.

doi:10.1101/2021.09.29.462391

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bioRxiv · 10.1101/2021.09.29.462391

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.

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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

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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.. 2021-10-01. Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.. https://doi.org/10.1101/2021.09.29.462391

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