Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma
Konda, P.; Weiss, C. N.; Cui, Y.; Matar, S.; Wang, J.; Nabil, Y. L.; Deodhar, R.; Li, J.; Horst, J.; Camp, S. Y.; Sheshdeh, A. B.; Hecht, J. L.; Einstein, D. J.; Rustagi, Y.; Nag, A.; Thorner, A. R.; Zhang, C.-Z.; Van Allen, E. M.; Signoretti, S.; Choueiri, T.; Viswanathan, S. R.
Show abstract
Renal cell carcinomas comprise multiple molecularly distinct cancers but most are treated empirically with therapies designed for clear cell RCC (ccRCC), the most common subtype, due to incomplete understanding of subtype-specific biology. We analyzed single-cell transcriptomes and chromatin accessibility profiles from translocation renal cell carcinoma (tRCC), an aggressive RCC defined by oncogenic TFE3 gene fusions. Unexpectedly, despite arising from a proximal tubule cell of origin similar to ccRCC, tRCCs display markedly distinct oncogenic programs and an immunosuppressive tumor microenvironment. tRCCs exhibit six conserved tumor meta-programs, including epithelial-mesenchymal transition and proximal tubule identity programs whose balance is regulated by TFE3 fusion activity. The fusion-driven EMT program drives a suppressive TME marked by progenitor-exhausted CD8+ T cells, anti-inflammatory SPP1+ macrophages, and matrix-associated fibroblasts (mCAFs). Our findings highlight unique TFE3 fusion-driven biology in tRCC, explaining its reduced immunotherapy responsiveness relative to ccRCC, and suggesting strategies for targeting fusion-driven oncogenic programs and TME reprogramming.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Cystatin C is glucocorticoid-responsive, directs recruitment of Trem2+ macrophages and predicts failure of cancer immunotherapy 97%
- Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures 96%
- Implications of noncoding regulatory functions in the development of insulinomas 96%
Similar papers in this journal
- Clonal evolution during metastatic spread in high-risk neuroblastoma 97%
- Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases 96%
- Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer 95%
"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.