bims-raghud 2025-11-30 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–11–30
nine papers selected by
Irene Sambri, TIGEM

MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma.
The Adaptation of Cancer Cells to Serum Deprivation Is Mediated by mTOR-Dependent Cholesterol Synthesis.
Clinical variation in Lowe syndrome: what and how?
Kidney Organoids: Current Advances and Applications.
Birt-Hogg-Dubé: CT characteristics of renal tumors in a rare syndrome.
Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.
YAP1 Depletion Enhances TAZ and its Complexation with TEAD4 and AP-1 Heterodimer C-JUN/FOSB to Promote Gastric Cancer Progression and Metastases.
Recurrent mTOR pathway alterations in renal cell carcinoma with hemangioblastoma-like features: A multi-institutional study of 9 cases with expanding morphologic spectrum.
TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.

Cell Rep. 2025 Nov 21. pii: S2211-1247(25)01270-7. [Epub ahead of print]44(12): 116499

MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma.

Diogo Dias, Erica Oliveira, Román Martí-Díaz, Sarah Andrews, Ana Chocarro-Calvo, Alice Bellini, Laura Mosteo, Yurena Vivas García, Jagat Chauhan, Linxin Li, José Manuel García-Martinez, José Neptuno Rodriguez-López, Silvya Stuchi Maria-Engler, Colin Kenny, Javier Martínez-Useros, Custodia García-Jiménez, Luis Sanchez-Del-Campo, Pakavarin Louphrasitthiphol, Colin R Goding.

  Cells can contain multiple related transcription factors targeting the same sequences, leading to potential regulatory cooperativity, redundancy, competition, or temporally regulated factor exchange. Yet, the differential biological functions of co-targeting transcription factors are poorly understood. In melanoma, three highly related transcription factors are co-expressed: the mammalian target of rapamycin complex 1 (mTORC1)-regulated TFEB and TFE3 (both key effectors of a wide range of metabolic and microenvironmental cues assumed to perform similar functions) and the microphthalmia-associated transcription factor (MITF), which controls melanoma phenotypic identity. Here, we reveal the functional specialization of MITF, TFE3, and TFEB and their impact on melanoma progression. Notably, although all bind the same sequences, each regulates different and frequently opposing gene expression programs to coordinate differentiation, metabolism, and protein synthesis and qualitatively and quantitatively impacts tumor immune infiltration. The results uncover a hierarchical cascade whereby microenvironmental stresses, including glucose limitation, lead MITF, TFEB, and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer.

Keywords:  CP: cancer; CP: genomics; MITF; TFE3; TFEB; melanoma; melanoma gene regulation; tumor immune infiltration

DOI:  https://doi.org/10.1016/j.celrep.2025.116499
Int J Mol Sci. 2025 Nov 12. pii: 10932. [Epub ahead of print]26(22):

The Adaptation of Cancer Cells to Serum Deprivation Is Mediated by mTOR-Dependent Cholesterol Synthesis.

Bayansulu Ilyassova, Nargiz Rakhimgerey, Saule Rakhimova, Nazerke Satvaldina, Asset Daniyarov, Ainur Akilzhanova, Ulykbek Kairov, Dinara Begimbetova, Dos D Sarbassov.

  Cancer cells can sustain survival independently of exogenous growth factors. To investigate their adaptation to serum deprivation, we analyzed transcriptomic responses in two cancer cell lines. Transcriptome analysis revealed upregulation of mRNAs encoding cholesterol biosynthesis enzymes. This was a critical adaptive response, as a pharmacological inhibition of the pathway with statin triggered a robust apoptotic cell death accompanied by generation of a mitochondrial reactive oxygen species. The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, is known to be engaged in controlling lipid biosynthesis. We detected the high polysomal and preribosomal peaks not only in serum-containing medium but also under serum deprivation, indicating a high rate of protein synthesis and ribosomal biogenesis independent of serum. In addition, the inhibition of mTOR kinase activity substantially reduced polysome abundance, with a more pronounced effect in serum-deprived cancer cells. Notably, the mTOR kinase inhibition also prevented the upregulation of the cholesterol synthesis enzyme that established a direct link between mTOR activity, protein synthesis, and cholesterol biosynthesis. Together, our results show that cancer cells adapt to serum withdrawal by activating the cholesterol synthesis pathway through mTOR-dependent regulation of gene expression and protein synthesis, underscoring a critical mechanism of survival under serum withdrawal.

Keywords:  apoptosis; cholesterol synthesis; mechanistic target of rapamycin complex 1 (mTORC1); polysomes; protein synthesis; reactive oxygen species; serum deprivation

DOI:  https://doi.org/10.3390/ijms262210932
Front Cell Dev Biol. 2025 ;13 1720452

Clinical variation in Lowe syndrome: what and how?

Eileen D Brewer.

  Lowe syndrome is an X-linked disorder caused by mutations of the OCRL gene which encodes the enzyme inositol polyphosphate-5-phosphatase OCRL (Ocrl1) and is expressed in almost all body cells. Clinical characteristics involve kidney, brain, eye, muscle, bone, teeth, testes, skin and thrombocytes. Clinical phenotypes are heterogenous among families and even among affected boys in the same family. All have kidney disease varying from severe manifestations of Fanconi syndrome to only low molecular weight proteinuria, hypercalciuria and little kidney disease in the first decade of life. All develop chronic kidney disease (CKD) that typically progresses slowly and reaches stages 4-5 after the second or third decade. All have neurological dysfunction, including developmental delay, marked intellectual impairment and behavioral abnormalities; ∼50% have seizure disorder. Congenital cataracts with or without glaucoma are almost always present. Less common features are hypotonia, bone abnormalities unrelated to kidney disease, abnormal teeth, cryptorchidism, skin cysts and mild bleeding disorder. Although Lowe syndrome is a monogenic disease, genotype/phenotype correlation is difficult to establish. Ubiquitous expression and complexity of Ocrl1 function likely contribute to the elusiveness of correlation. Additionally, two diseases, Lowe syndrome and Dent disease type 2, result from mutations in the OCRL gene with some overlap in affected exons. Growing research in molecular and conformational abnormalities of Ocrl1 variants is triggering development of cell phenotype models for further study. Understanding how genotype leads to clinical phenotype has potential to provide better predictors of Lowe syndrome severity and specific therapeutic strategies for different subsets of affected patients.

Keywords:  Lowe syndrome; dent disease 2; genotype; kidney; neurologic; ocrl; oculocerobrorenal; phenotype

DOI:  https://doi.org/10.3389/fcell.2025.1720452
Life (Basel). 2025 Oct 29. pii: 1680. [Epub ahead of print]15(11):

Kidney Organoids: Current Advances and Applications.

Hiroyuki Nakanoh, Kenji Tsuji, Kazuhiko Fukushima, Naruhiko Uchida, Soichiro Haraguchi, Shinji Kitamura, Jun Wada.

  Kidney organoids, derived from stem cells, including pluripotent stem cells and adult progenitor cells, have been reported as three-dimensional in vitro models that reflect key aspects of kidney development, structure, and function. Advances in differentiation protocols and tissue engineering have enabled the generation of organoids that exhibit nephron-like structures, including glomerular and tubular structures. Kidney organoids have been widely applied in several directions, including disease modeling and therapeutic screening, drug nephrotoxicity evaluation, and regenerative medicine. In particular, kidney organoids offer a promising platform for studying genetic kidney diseases, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), by allowing patient-specific modeling for the analysis of pathophysiology and therapeutic screening. Despite several current limitations, such as incomplete maturation, lack of full nephron segmentation, and variability between protocols and cell conditions, further technological innovations such as microfluidics and bioengineering may refine kidney organoid systems. This review highlights recent advances in kidney organoid research, outlines major applications, and discusses future directions to enhance their physiological relevance, functional maturity, and translational integration into preclinical and clinical nephrology.

Keywords:  disease modeling; drug screening; drug toxicity; kidney organoid; regenerative medicine; stem cell

DOI:  https://doi.org/10.3390/life15111680
Abdom Radiol (NY). 2025 Nov 27.

Birt-Hogg-Dubé: CT characteristics of renal tumors in a rare syndrome.

Mahshid Golagha, Negin Jarrah, Shiva Singh, Aryan Zahergivar, Pouria Yazdian Anari, Elizabeth C Jones, Maria J Merino, W Marston Linehan, Ashkan A Malayeri.

   PURPOSE: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic condition characterized by pathogenic variation in the folliculin (FLCN) gene on chromosome 17p11.2. Individuals affected with BHD are at risk to develop renal cysts and masses (13-34% of cases); renal masses are mostly hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, or oncocytomas. This study aims to investigate the computed tomography (CT) manifestations of renal masses associated with BHD syndrome.
METHODS: Multiphase CT imaging of patients with BHD syndrome who underwent renal surgery between March 2000 and December 2020 was evaluated. Imaging characteristics of the masses, including laterality, diameter, margin, tumor configuration, homogeneity, longitudinal location, percentage of tumor deepening into the kidney, location relative to the rim, presence of central scar, fat, calcification, pre-contrast density, and enhancing pattern, were recorded.
RESULTS: This investigation included 169 renal masses from 30 adult patients with BHD syndrome (mean age 53 ± 12 years, 15 males). Surgical laterality was 36.7% left, 40.0% right, and 23.3% bilateral. The mean diameter of the examined masses was 2.71 ± 1.62 cm. Growth rate analysis of 132 masses showed a growth rate of 0.04 cm per year (95% CI: 0.01- 0.07). The majority of masses selected for analysis (94.1%) were hybrid tumors. In the hybrid masses, 98.8% were predominantly solid, 68.0% were homogeneous, and 73.4% had well-defined margins. Exophytic masses were predominant (79.9%), primarily located on the lateral rim (45.6%). Longitudinally, 32.6% were in the upper pole, 36.0% interpolar, and 30.5 in % lower pole. Central scar was present in 9.5%, calcification in 4.1%, and none contained fat. In the pre-contrast phase, the mean density of masses was 36.1 HU ± 8.9. Normalized enhancement based on the renal cortex was lower in the venous than the arterial phase (0.73 vs. 0.88).
CONCLUSIONS: Our analysis confirmed that while BHD-associated renal masses demonstrate diversity in CT presentations, most are solid, homogeneous, exophytic, exhibit a pre-contrast density of 36.1 HU ± 8.9, and have well-defined margins in the lateral rim.

Keywords:  Birt-Hogg-Dubé syndrome; CT scan; FLCN; Folliculin; Hybrid oncocytic/chromophobe; Hybrid renal cell carcinoma; Renal cell carcinoma

DOI:  https://doi.org/10.1007/s00261-025-05303-1
Am J Physiol Cell Physiol. 2025 Nov 27.

Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.

Sara Petrosino, Paolo Grumati.

  Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential metabolites. The glucose transporter 1 (GLUT1) is among the proteins that can undergo autophagy-mediated degradation in response to metabolic stimuli. GLUT1 is essential for cellular glucose supply in several tissues. Notably, GLUT1 facilitates glucose transport across the blood-brain barrier, creating a concentration gradient from the bloodstream into the brain's interstitial fluid. The presence of GLUT1, at the plasma membrane, is the first step in initiating glucose uptake and driving glycolysis inside the cell. Glycolysis can be initiated in response to several stimuli, including glucose availability, autophagy inhibition and growth factor accessibility. In this review, we highlight recently described mechanisms that govern the subcellular distribution of GLUT1 with a focus on autophagy-mediated trafficking. Understanding how autophagy coordinates GLUT1 sorting in response to metabolic demands may uncover novel therapeutic targets for metabolic disorders characterized by dysregulated GLUT1 trafficking.

Keywords:  Autophagy; GLUT1; Metabolism; Signalling; Trafficking

DOI:  https://doi.org/10.1152/ajpcell.00551.2025
bioRxiv. 2025 Nov 14. pii: 2025.11.13.683933. [Epub ahead of print]

YAP1 Depletion Enhances TAZ and its Complexation with TEAD4 and AP-1 Heterodimer C-JUN/FOSB to Promote Gastric Cancer Progression and Metastases.

Jingjing Wu, Dipti Athavale, Curt Balch, Junsong Zhao, Gengyi Zou, Yibo Fan, Yanting Zhang, Joseph Zhao, Mikel Ghelfi, Anthony Pompetti, Gennaro Calendo, Ailing Scott, Shan Shao, Xiaodan Yao, Melissa Pool Pizzi, Christopher Vellano, Vladimir Khazak, Sheng Zhang, Timothy Anthony Yap, Shilpa S Dhar, Raghav Sundar, Francis Spitz, Generosa Grana, Jaffer A Ajani, Shumei Song.

Background Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumour progression, immunosuppression and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumours, however, the expression profiles of Hippo coactivators YAP1, TAZ and their transcriptional factors TEADs in gastric cancer peritoneal metastases (GCPMs) and their therapeutic value are unknown. Objective To determine expression status of YAP1, TAZ and TEADs in GCPMs; and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumour activity compared with inhibition of either coactivator alone. Design Expression of YAP1, TAZ and TEADs was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects in vitro and in vivo. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumour efficacy was validated in patient-derived xenograft (PDX) and KPLuc2 syngeneic models. Results YAP1, TAZ, and TEADs were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion in vitro, and tumor growth in vivo. Increased TAZ complexation with TEAD4 and AP1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes. Conclusions These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPMs, a highly lethal disease with an urgent need for novel treatment options.

DOI: https://doi.org/10.1101/2025.11.13.683933
Virchows Arch. 2025 Nov 24.

Recurrent mTOR pathway alterations in renal cell carcinoma with hemangioblastoma-like features: A multi-institutional study of 9 cases with expanding morphologic spectrum.

Ming Zhao, Xiaoqun Yang, Xiaona Yin, Tianshi Ma, Hongtao Jin, Jiayun Xu, Huizhi Zhang, Suying Wang.

  Renal hemangioblastoma (HB) is a rare extra-central nervous system mesenchymal neoplasm molecularly defined by recurrent mTOR pathway alterations and lacking VHL abnormalities, distinct from its central nervous system counterpart. While rare renal cell carcinomas (RCCs) exhibiting HB-like features have been documented, their clinicopathological spectrum, biological behavior, and molecular underpinnings remain incompletely characterized. This study characterizes a multi-institutional series of 9 cases of RCC with HB-like features. All tumors presented as well-circumscribed, solitary renal masses (median size, 2.6 cm), with 8 out of 9 cases demonstrating thick fibromuscular capsules. All cases uniformly lacked necrosis, mitotic activity, and vascular invasion. Histologically, the tumors demonstrated a variable proportion of the RCC component (5-50% tumor volume, mean:10%) with clear to pale eosinophilic cells forming tubules, acini, or tubulocystic structures blending with the dominant HB-like component; one case showed discrete compartmentalization of the RCC component, forming distinct papillary and tubulocystic structures adjacent to HB-like areas. Immunohistochemically, RCC components expressed epithelial markers (AE1/AE3, cytokeratin 7, CAM5.2), while HB-like components expressed stromal markers (α-inhibin, S100 protein). Critically, both components consistently expressed PAX8, vimentin, carbonic anhydrase IX, CD10, neuron-specific enolase, and GPNMB (8/9). Targeted next-generation sequencing revealed universal mTOR pathway alterations: mutually exclusive MTOR mutations (5 cases) or TSC2 mutations (4 cases), with no VHL alterations or 3p25 deletions identified. Over a median follow-up of 50 months (range, 4-114 months), all patients remained disease-free. Our study confirms that RCC with HB-like features represents a distinct morphological pattern within the HB to RCC with fibromyomatous stroma continuum and establishes its expanded morphological spectrum and indolent biological behavior.

Keywords:   MTOR ; TSC ; GPNMB; Hemangioblastoma; Immunohistochemistry; MTOR pathway; Next-generation sequencing; Renal cell carcinoma with fibromyomatous stroma; Renal neoplasm

DOI:  https://doi.org/10.1007/s00428-025-04362-5
Free Radic Biol Med. 2025 Nov 23. pii: S0891-5849(25)01390-5. [Epub ahead of print]243 398-413

TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.

Haoyu Zhang, Yuchen Jia, Zheng Wang, Jie Li, Xiaozhou Xie, Yixuan Ding, Feng Cao, Fei Li.

  Mitophagy, oxidative stress, and ferroptosis are critical processes in the development of acute pancreatitis (AP). Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, plays a central role in the pathogenesis of AP. However, its specific regulatory mechanisms within the mitophagy-oxidative stress-ferroptosis network remain incompletely understood. This study investigated the therapeutic potential of ginkgetin (GK), a natural TFEB activator, in AP. The results demonstrated that GK activated TFEB and subsequently significantly alleviated pathological damage in AP in vivo and effectively inhibited acinar cell death in vitro. Further mechanistic studies revealed that TFEB activation markedly improved impaired autophagic flux in AP, enhanced mitophagy, and simultaneously suppressed ferroptosis and oxidative stress. Specifically, TFEB upregulated the expression of the lysosomal marker LAMP1 to restore autophagy-lysosome function and induced the expression of BNIP3, a key mitophagy receptor, thereby enhancing mitochondrial quality control, restoring mitochondrial function, and ultimately mitigating oxidative stress and ferroptosis. Functional experiments confirmed that TFEB exerts its protective effects through nuclear translocation. When nuclear translocation was blocked by a C270S mutation-a mutation that disrupts TFEB dissociation from 14-3-3 proteins and subsequent nuclear localization-TFEB's regulatory roles in autophagy, mitophagy, ferroptosis, and oxidative stress were significantly inhibited. This study elucidates that TFEB, through nuclear translocation, not only restores basal autophagy but also enhances mitophagy, thereby collectively inhibiting oxidative stress and ferroptosis and alleviating the progression of AP. These findings provide a novel therapeutic strategy for AP.

Keywords:  Acute pancreatitis; Ferroptosis; Ginkgetin; Mitophagy; Oxidative stress; TFEB

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.045