Biology subjects

Asrani, K.

Publications and source records attributed to Asrani, K..

3 recordsLinked to original sources

bioRxiv2026

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

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.

cancer biology↗

bioRxiv2024

SFPQ-TFE3 gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis

The MiT/TFE family gene fusion proteins, such as SFPQ-TFE3, drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models for SFPQ-TFE3-related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of human SFPQ-TFE3 using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death. In contrast, post-natal induction of SFPQ-TFE3 in renal tubular epithelial cells using Pax8 ERT-Cre induces infiltrative epithelioid tumors, which morphologically and transcriptionally resemble human PEComas. As seen in MiT/TFE fusion-driven human tumors, SFPQ-TFE3 expression is accompanied by the strong induction of mTORC1 signaling, which is partially amino acid-sensitive and dependent on increased SFPQ-TFE3-mediated RRAGC/D transcription. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity in renal tubular epithelial cells, with rapid down-regulation of the critical PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and concomitant up-regulation of PEComa differentiation markers in transgenic mice, human cell line models and human tRCC. Pharmacologic or genetic inhibition of mTOR signaling downregulates expression of the SFPQ-TFE3 fusion protein and rescues nephric lineage marker expression and transcriptional activity in vitro. These data provide evidence of a potential epithelial cell-of-origin for TFE3-driven PEComas and highlight a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney, expanding our understanding of the pathogenesis of MiT/TFE-driven tumors.

cancer biology↗

bioRxiv2019

Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 non-malformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = 0.03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

genetics↗