bims-raghud 2025-10-05 papers

Nat Commun. 2025 Oct 03. 16(1): 8822

SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis.

MiT/TFE gene fusions like SFPQ-TFE3 drive both epithelial (translocation RCC) and mesenchymal (PEComas) neoplasms. However, no mouse models for SFPQ-TFE3-related tumors exist and the underlying mechanisms of lineage plasticity remain unclear. Here, we demonstrate that constitutive murine renal expression of SFPQ-TFE3 disrupts kidney development with early neonatal renal failure and death, while post-natal induction induces infiltrative epithelioid tumors, that morphologically and transcriptionally resemble human PEComas, with strong activation of mTORC1 signaling via increased V-ATPase expression. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity, with down-regulation of the PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and up-regulation of PEComa differentiation markers in transgenic mice, cell lines and human tRCC. mTOR inhibition downregulates SFPQ-TFE3 expression and rescues PAX8 expression and transcriptional activity in vitro. These data provide evidence of an epithelial cell-of-origin for TFE3-driven PEComas, highlighting a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney.

DOI: https://doi.org/10.1038/s41467-025-63885-2

Sci Adv. 2025 Oct 03. 11(40): eadw7376

The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

DOI: https://doi.org/10.1126/sciadv.adw7376

Nat Commun. 2025 Sep 30. 16(1): 8712

RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma.

Lei Guo, Rongjie Zhao, Yi-Tsang Lee, Junhua Huang, James Wengler, Logan Rivera, Tingting Hong, Tianlu Wang, Kunjal Rathod, Ashley Suris, Yitian Wu, Xiaoli Cai, Rui Wang, Yubin Zhou, Yun Huang.

Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression.

DOI: https://doi.org/10.1038/s41467-025-63761-z

Exp Mol Med. 2025 Oct 01.

The multifaceted role of YAP in the tumor microenvironment and its therapeutic implications in cancer.

Hyung-Sik Kim, Jeong-Seok Nam.

The tumor microenvironment (TME) plays a critical role in cancer progression, immune evasion and therapeutic resistance. The transcriptional coactivators YAP and TAZ, key effectors of the Hippo signaling pathway, have emerged as central regulators of TME remodeling. YAP/TAZ are activated in both tumor and stromal compartments, where they function as mechanotransducers and integrate canonical Hippo pathway suppression, noncanonical microenvironmental cues and genetic or epigenetic signals to drive transcriptional programs. These changes collectively facilitate tumor immune evasion. YAP/TAZ further promote angiogenesis and upregulate PD-L1 expression in tumor cells and cancer-associated fibroblasts, and a subset of immunosuppressive cells in the TME, contributing to resistance to ICB. In addition to their tumor-intrinsic and stromal functions, YAP/TAZ impair antitumor immunity by altering immune cell differentiation and dampening effector responses. Targeting the YAP/TAZ-TEAD axis has shown potential efficacy when combined with immune checkpoint inhibitors, chimeric antigen receptor T cell therapies and tumor vaccines. Although challenges such as tumor selectivity and resistance mechanisms persist, advances in single-cell and spatial transcriptomics are enabling the dissection of YAP/TAZ-regulated networks and guiding the development of more precise therapeutic strategies. Collectively, YAP/TAZ inhibition offers a promising avenue to reprogram the TME and enhance the efficacy of next-generation cancer immunotherapies.

DOI: https://doi.org/10.1038/s12276-025-01551-9