TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Kaushal V. Asrani; Juhyung Woo; Thiago Vidotto; Kewen Feng; Alan Lorenzetti; Eddie L. Imada; Huili Li; Rajan Singh; Anand K Thotakura; Sangeeta Ray; Lia Oliveira; Adrianna Amaral; Vikrant Palande; Ravi Kumar Anchoori; Jayaprakash Mandal; Roy Elias; Christopher J. Thoburn; Md. Masud Rana; Hrishikesh Nagbhushan Gangule; Alexander Gao; Pornima Phatak; James Donahue; Yasser M. A. Ged; Nirmish Singla; John Copland; Laura Schmidt; William Marston Linehan; Pedram Argani; Tamara Lotan

doi:10.64898/2026.09.18.752493

Cancer BiologybioRxivSep 22, 2026

Preprint

TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Kaushal V. Asrani iD, Juhyung Woo iD, Thiago Vidotto iD, Kewen Feng, Alan Lorenzetti, Eddie L. Imada iD, Huili Li, Rajan Singh iD, Anand K Thotakura, Sangeeta Ray, Lia Oliveira, Adrianna Amaral, Vikrant Palande iD, Ravi Kumar Anchoori, Jayaprakash Mandal iD, Roy Elias, Christopher J. Thoburn iD, Md. Masud Rana, Hrishikesh Nagbhushan Gangule, Alexander Gao, Pornima Phatak iD, James Donahue, Yasser M. A. Ged iD, Nirmish Singla iD, John Copland, , Tamara Lotan

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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