bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–06–15
thirteen papers selected by
Irene Sambri, TIGEM
  1. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
  2. Folliculin deletion in the mouse kidney results in cystogenesis of the loops of Henle via aberrant TFEB activation.
  3. Kidney organoid models of Polycystic Kidney Disease - challenges and future directions.
  4. Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.
  5. Nuclear localization of YAP in pancreatic cancer: More players besides Hippo pathway.
  6. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
  7. Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.
  8. Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.
  9. YAP, TAZ, and Hippo-Dysregulating Fusion Proteins in Cancer.
  10. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  11. Dapagliflozin in addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome.
  12. Mitochondrial micro RNAs: Crucial players in carcinogenesis.
  13. Case Report: Extrarenal TFE3 fusion-related renal cell carcinoma.
  1. Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]
    AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
    Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.
      Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.
    Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
  2. Am J Pathol. 2025 Jun 09. pii: S0002-9440(25)00192-0. [Epub ahead of print]
    Folliculin deletion in the mouse kidney results in cystogenesis of the loops of Henle via aberrant TFEB activation.
    Ola Shalaby, Tomoko Ohmori, Koichiro Miike, Shunsuke Tanigawa, Luh Ade Wilan Krisna, Alessia Calcagnì, Andrea Ballabio, Yoshiaki Kubota, Laura S Schmidt, W Marston Linehan, Takaaki Ito, Masaya Baba, Ryuichi Nishinakamura.
      The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé (BHD) syndrome, which is characterized by a variety of manifestations including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. We report here that nephron-specific Flcn knockout mice exhibit cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen lined by enlarged epithelia. Single-cell RNA sequencing revealed many upregulated genes, especially in the knockout LoH. These genes include those related to lysosomal activity and mTORC1 activation and are likely targets of TFE3/TFEB. While the double Flcn/Tfe3 knockout only ameliorates the glomerular cysts, the double Flcn/Tfeb knockout largely reverses most of the phenotypes along the entire nephron. Thus, Flcn deletion leads to cystogenesis via aberrant TFEB activation. Our findings reveal the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and shed light on the pathogenesis of BHD syndrome.
    DOI:  https://doi.org/10.1016/j.ajpath.2025.05.010
  3. Am J Physiol Renal Physiol. 2025 Jun 11.
    Kidney organoid models of Polycystic Kidney Disease - challenges and future directions.
    Humayra Afrin, Usama Qamar, Jielu Hao Robichaud, Mohamed Ellabbad, Peter C Harris, Navin Gupta.
      Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSC) of patients that bear naturally occurring mutations or from CRISPR mutant hPSCs by virtue of their genetic tractability. PKD is the leading inheritable cause of kidney failure (KF), accounting for an ~5-10% of the kidney transplant and dialysis needs worldwide. PKD is a disorder of considerable genetic heterogeneity, comprised of typical adult-onset autosomal dominant (ADPKD) and fetal-onset autosomal recessive (ARPKD) forms which share pathomechanisms. Despite advances in our understanding of the genetic and molecular underpinnings of PKD, the limited clinical treatment options have raised concerns regarding the faithfulness of preclinical models. Kidney organoids have emerged as a promising platform to study PKD by mimicking human-specific responses, enabling personalized medicine, and supporting high-throughput screens. Yet valid criticisms have related to the relative immaturity of kidney organoids for modeling adult-onset forms of PKD, the faithfulness of organoids in modelling the cystic distribution of afflicted patients, and their batch-to-batch variability limiting experimental reproducibility. Here we summarize a decade of kidney organoid models of PKD, emphasizing their role in advancing translational and therapeutic applications while addressing their limitations and future potential.
    Keywords:  Cyst formation; Genotype; Kidney organoid; Polycystic kidney disease; Therapeutic screen
    DOI:  https://doi.org/10.1152/ajprenal.00116.2025
  4. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2424679122
    Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.
    Kelly M O'Leary, Tomasz Slezak, Anthony A Kossiakoff.
      Subcellular compartmentalization is integral to the spatial regulation of mechanistic target of rapamycin (mTOR) signaling. However, the biological outputs associated with location-specific mTOR signaling events are poorly understood and challenging to decouple. Here, we engineered synthetic intracellular antibodies (intrabodies) that are capable of modulating mTOR signaling with genetically programmable spatial resolution. Epitope-directed phage display was exploited to generate high affinity synthetic antibody fragments (Fabs) against the FKBP12-Rapamycin binding site of mTOR (mTORFRB). We determined high-resolution crystal structures of two unique Fabs that discriminate distinct conformational states of mTORFRB through recognition of its substrate recruitment interface. By leveraging these conformation-specific binders as intracellular probes, we uncovered the structural basis for an allosteric mechanism governing mTOR complex 1 (mTORC1) stability mediated by subtle structural adjustments within mTORFRB. Furthermore, our results demonstrated that synthetic binders emulate natural substrates by employing divergent yet complementary hydrophobic residues at defined positions, underscoring the broad molecular recognition capability of mTORFRB. Intracellular signaling studies showed differential time-dependent inhibition of S6 kinase 1 and Akt phosphorylation by genetically encoded intrabodies, thus supporting a mechanism of inhibition analogous to the natural product rapamycin. Finally, we implemented a feasible approach to selectively modulate mTOR signaling in the nucleus through spatially programmed intrabody expression. These findings establish intrabodies as versatile tools for dissecting the conformational regulation of mTORC1 and should be useful to explore how location-specific mTOR signaling influences disease progression.
    Keywords:  allosteric; inhibition; intrabody; mTOR; spatial
    DOI:  https://doi.org/10.1073/pnas.2424679122
  5. Cancer Lett. 2025 Jun 06. pii: S0304-3835(25)00431-8. [Epub ahead of print] 217864
    Nuclear localization of YAP in pancreatic cancer: More players besides Hippo pathway.
    Yiping Xie, Cheng Qin, Xiangyu Zhang, Zeru Li, Bangbo Zhao, Tianyu Li, Yutong Zhao, Yutong Yan, Haoyu Shi, Lirui Huang, Weibin Wang.
      The Yes-associated protein (YAP) is a critical regulator of organ size and a key player in tumorigenesis, with its activity primarily governed by the Hippo signaling pathway. YAP mainly functions as a transcriptional co-activator, therefore its activity is closely related to its nuclear localization. Recent studies have shed light on mechanisms that regulate YAP's nuclear localization and activation, independent of the Hippo pathway. Beyond its role in development and tissue homeostasis, YAP's dysregulation is implicated in various cancers, including pancreatic cancer, one of the most lethal cancers. Activated YAP translocates to the nuclear of cancer cell, subsequently promotes expression of downstream genes involved in tumor growth, metastasis, and resistance to chemotherapy, etc. Moreover, YAP can also function as a transcription suppressor, indicating its context-dependent role in cancer. A thorough understanding of YAP regulation in pancreatic cancer could offer new insights for targeted therapy approaches. Here this review concludes recent findings on Hippo-independent regulation of YAP nuclear localization and the role of YAP in pancreatic cancer progression.
    DOI:  https://doi.org/10.1016/j.canlet.2025.217864
  6. Nature. 2025 Jun 11.
    Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
    Dylan Calhoon, Lingjie Sang, Fubo Ji, Divya Bezwada, Sheng-Chieh Hsu, Feng Cai, Nathaniel Kim, Amrita Basu, Renfei Wu, Anastasia Pimentel, Bailey Brooks, Konnor La, Ana Paulina Serrano, Daniel L Cassidy, Ling Cai, Vanina Toffessi-Tcheuyap, Maryam E Moussa, Winnie Uritboonthai, Linh Truc Hoang, Meghana Kolli, Brooklyn Jackson, Vitaly Margulis, Gary Siuzdak, James Brugarolas, Ian Corbin, Derek A Pratt, Ryan J Weiss, Ralph J DeBerardinis, Kıvanç Birsoy, Javier Garcia-Bermudez.
      Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41586-025-09162-0
  7. Cells. 2025 May 28. pii: 794. [Epub ahead of print]14(11):
    Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.
    Nikola Pavlović, Marinela Križanac, Marko Kumrić, Katarina Vukojević, Joško Božić.
      Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia-reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial-ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions-ranging from Drp1 inhibition to mitochondrial transplantation-hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies.
    Keywords:  CAKUT; acute kidney injury; chronic kidney disease; mitochondria; mitophagy; renal pathology
    DOI:  https://doi.org/10.3390/cells14110794
  8. Autophagy. 2025 Jun 12.
    Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.
    Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li.
      Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8+ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.
    Keywords:  Cholesterol; PD-L1; TFEB; immune evasion; lysosome; protein degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2519066
  9. Annu Rev Cancer Biol. 2024 Jun;8 331-350
    YAP, TAZ, and Hippo-Dysregulating Fusion Proteins in Cancer.
    Jordan H Driskill, Josephine K Dermawan, Cristina R Antonescu, Duojia Pan.
      Gene fusions are well-known drivers of cancer and are potent targets for molecular therapy. An emerging spectrum of human tumors harbors recurrent and pathognomonic gene fusions that involve the transcriptional coactivator YAP1 (which encodes the protein YAP) or its paralog WWTR1 (which encodes the protein TAZ). YAP and TAZ are frequently activated in cancer and are the transcriptional effectors of the Hippo pathway, a highly conserved kinase cascade that regulates diverse functions such as organ size, development, and homeostasis. In this review, we discuss the tumors that have YAP, TAZ, or other Hippo-dysregulating fusion proteins; the mechanisms of these fusion proteins in driving their respective tumors; and the potential vulnerabilities of these chimeric oncoproteins across cancers of many origins. Furthermore, as new YAP1 and WWTR1 gene fusions are discovered, we provide a framework to predict whether the resulting protein product is likely to be oncogenic.
    Keywords:  Hippo pathway; WWTR1/TAZ; YAP1; cancer; gene fusions; sarcoma
    DOI:  https://doi.org/10.1146/annurev-cancerbio-061223-094639
  10. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  11. Am J Physiol Renal Physiol. 2025 Jun 11.
    Dapagliflozin in addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome.
    Kana N Miyata, Denise M Smith, Michifumi Yamashita, Shimok Kim, F Andrea Yeargin, Melisa Beganovic, Shao-Ling Zhang, John S D Chan, Jeffrey H Miner, Daniel N Leal, Jian-Ping Li, Jonathan Bruno.
      Renin-angiotensin-aldosterone system inhibitors (RAASi) have been the most extensively studied treatment for Alport syndrome, demonstrating established benefits for renal function and survival in both animals and humans. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) slow chronic kidney disease progression, but their renoprotective mechanisms in non-diabetic glomerular diseases remain unclear. Here, we investigated whether combining dapagliflozin (an SGLT2i) with ramipril (an angiotensin-converting enzyme Inhibitor) enhances kidney protection compared to ramipril alone in Col4α3 knockout (KO) mice, a murine model of Alport syndrome. Alport and wild-type (WT) mice (129S1/SvImJ) received dapagliflozin (1.5 mg/kg/day), ramipril (10 mg/kg/day), or both (D/R) via drinking water from 4 weeks of age. Mice were studied until 10 weeks of age (short-term, N=13-15/sex/group), 15 weeks of age (long-term, N=11-12/sex/group), or death (survival, N=8-12/sex/group). By 10 weeks, Alport mice exhibited weight loss, reduced glomerular filtration rate (GFR), increased BUN, and albuminuria, which were mitigated by ramipril and D/R but not by dapagliflozin. At 15 weeks, D/R-treated mice had better renal function and histopathology than those on ramipril alone. D/R also extended survival compared to ramipril alone (median 157 vs. 125 days, p<0.01). Kidneys from D/R-treated mice exhibited reduced lipid accumulation and cell senescence. In conclusion, combining dapagliflozin with ramipril better preserves renal function and architecture and prolongs survival in Col4α3 KO Alport mice compared to ramipril alone.
    Keywords:  Alport Syndrome; SGLT2 inhibitors; Senescence; renin angiotensin system
    DOI:  https://doi.org/10.1152/ajprenal.00130.2025
  12. Oncol Res. 2025 ;33(6): 1301-1321
    Mitochondrial micro RNAs: Crucial players in carcinogenesis.
    Ashutosh Kumar Maurya, Anjali Sangeeth, Rabina Punathil, R Grace Raji, V B Sameer Kumar.
      Carcinogenesis is a multilevel process characterized by genetic and epigenetic alterations, thus contributing to uncontrolled proliferation that eventually leads to cancer. The process of carcinogenesis involves an intricate dis-orchestration in the expression of both, coding and non-coding sequences and is also dependent on the reprogramming of energy metabolism as both direct and indirect consequence of oncogenic mutations. Dysregulated mitochondrial energetics is an important hallmark of cancer, where cancer cells switch to the glycolytic pathway as an alternate source of energy to support the continuous energy supply needed for their indefinite growth. Even though functional mitochondria are indispensable for cancer cells, cancer cells exhibit different bioenergetics transitions based on the development status of cells undergoing carcinogenesis. Although the role of coding sequences in regulating energy metabolism shift is well studied, the role of non-coding sequences in modulating energy metabolism is still unclear. MicroRNAs (miRNAs), usually present in the nucleus and cytoplasm, have now been reported to localize in the mitochondria also known as, mitochondrial miRNAs (MitomiRs), which can originate either from the nuclear or mitochondrial genome. MitomiRs are reported to be associated with both oncogenic and tumor-suppressive functions. MitomiRs can target metabolic pathway-related protein-coding genes to alter cellular metabolism and promote carcinogenesis. Several mitomiRs like miR-1, miR-133, miR-128, and miR-21 have been reported to be involved in normal physiology, survival, and pathology. Since energy metabolism is one of the most important hallmarks of carcinogenesis and its underlying mechanism involves dysregulation of mitochondrial metabolism, we have tried to collate the importance of mitomiRs in the process of cancer energy metabolism and carcinogenesis.
    Keywords:  Carcinogenesis; Electron Transport Chain (ETC); Glycolytic switch; Mitochondrial microRNAs (MitomiRs)
    DOI:  https://doi.org/10.32604/or.2025.055945
  13. Front Oncol. 2025 ;15 1592042
    Case Report: Extrarenal TFE3 fusion-related renal cell carcinoma.
    Zhouliang Yang, Ting Li, Kejun Lv, Xiaowei Zhang.
       Introduction: Transcription factor binding to IGHM enhancer 3 (TFE3) fusion-related renal cell carcinoma (TFE3-RCC) is a rare subtype of RCC. Its pathogenesis is primarily associated with chromosomal translocations resulting in TFE3 fusions. TFE3-RCC is most commonly observed in adolescents and young adults, with a higher incidence in women than in men. Typically, TFE3-RCC initially presents as painless hematuria, an abdominal mass, or with systemic symptoms. In recent years, with advancements in molecular diagnostic techniques, the diagnosis rate of TFE3-RCC has increased. However, extrarenal occurrences of TFE3-RCC remain rare. PRCC can fuse with TFE3 causing PRCC-TFE3 fusion-related RCC, a unique subtype of TFE3-RCC.
    Case presentation: We report a case of PRCC-TFE3 RCC in a 29-year-old woman who was hospitalized owing to a mass in her upper abdomen. To our knowledge, this is the second reported instance of an extrarenal occurrence. Imaging revealed a large mass in the left retroperitoneum, and postoperative pathology revealed that the tumor cells were either epithelioid- or spindle-shaped, with large nuclei, prominent nucleoli, and abundant chromatin. The cells were densely arranged in nests or sheets, with abundant eosinophilic or amphophilic cytoplasm. Immunohistochemical analysis revealed diffuse and strong nuclear positivity for TFE3 but negativity for carbonic anhydrase IX (CAIX). Fluorescence in situ hybridization did not detect a TFE3 break, but RNA sequencing confirmed the presence of a PRCC-TFE3 fusion.
    Conclusion: The diagnosis of TFE3-RCC requires a comprehensive evaluation of histological features, immunohistochemical markers, and molecular testing. PRCC-TFE3 RCC is highly aggressive with a high recurrence rate and poor prognosis in adults. Surgical resection is the primary treatment for localized lesions. However, close follow-up is necessary owing to a high risk of recurrence and metastasis. Targeted therapies and immunotherapies are potential treatment options for patients with advanced or metastatic disease.
    Keywords:  TFE3 fusion; extrarenal; pathology; renal cell carcinoma; surgery
    DOI:  https://doi.org/10.3389/fonc.2025.1592042
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