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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma
Prathyusha Konda1,2, Alexandra J Wakolbinger1, Yantong Cui1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
Renal cell carcinomas (RCC) 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. We show that, despite arising from a proximal tubule cell of origin similar to ccRCC, tRCCs display distinct oncogenic programs and an immunosuppressive tumor microenvironment (TME). tRCCs exhibit six conserved tumor meta-programs, including epithelial-mesenchymal transition (EMT) 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. 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.
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