TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma
Asrani, K.; Woo, J.; Vidotto, T.; Feng, K.; Lorenzetti, A.; Imada, E.; Li, H.; Singh, R.; Thotakura, A.; Ray, S.; Oliveira, L.; Amaral, A.; Palande, V.; Anchoori, R.; Mandal, J.; Elias, R.; Thoburn, C.; Rana, M. M.; Gangule, H. N.; Gao, A.; Phatak, P.; Donahue, J.; Ged, Y.; Singla, N.; Copland, J.; Schmidt, L.; Linehan, W. M.; Argani, P.; Lotan, T.
Show abstract
Xp11.2 translocation RCC [Xp11.2 tRCC]) is an underdiagnosed and aggressive subtype of RCC with few specific or targeted therapies. The transmembrane glycoprotein CD44 is an emerging target in many advanced malignancies, and with its ligand OPN (SPP1), is a crucial driver of cancer progression, stemness, metastasis, and immune suppression. Here we show that common TFE3-fusions [ including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3] are associated with upregulated expression of CD44 and SPP1, as observed in multiple human and murine bulk transcriptomic studies and a murine tRCC snRNA-Seq dataset. CD44 and/or SPP1 protein expression were also upregulated in murine models of transgenic tRCC kidneys and urine specimens, patient-derived cell lines and human tRCC cases, by immunoblotting and/or IHC. Transient deletion of CD44 was associated with profound and specific suppression of tRCC cell line growth, with decreased mTOR signaling. These data suggest that CD44 and/or SPP1 may potentially drive tumorigenesis in tRCC.
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