BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Language: Английский

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Identification of PLAC1 as a prognostic biomarker and molecular target in clear cell renal cell carcinoma

Cellular Signalling, Journal Year: 2025, Volume and Issue: 127, P. 111606 - 111606

Published: Jan. 13, 2025

Clear cell renal carcinoma (ccRCC) is a common clinical tumor of the urinary system. The lack effective diagnostic and treatment options poses serious challenge to treatment. Therefore, identifying molecular targets has become one potential means treat this disease. Firstly, analysis TCGA database found that PLAC1 was abnormally highly expressed in ccRCC negatively correlated with patient prognosis. Western blotting immunofluorescence experiments further verified patients, knockdown inhibited development vitro. Last, high-throughput virtual screening technology (HTVS) performed identify two inhibitors ，AmB Cana, which were able reduce expression progression ccRCC. In conclusion, current investigation indicated could serve as prognostic biomarker, AmB Cana inhibit by reducing PLAC1, making it therapeutic option for

Language: Английский

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PILOT-GM-VAE: Patient-Level Analysis of single cell Disease Atlas with Optimal Transport of Gaussian Mixture Variational Autoencoders

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Motivation The analysis of single cell disease atlases represents a challenge due to the presence batch effects, low quality samples, and multi-scale nature data, i.e., samples are described by different distributions. Because these, few computational approaches performing sample-level progression so far. Results Here, we introduce Patient-Level Analysis with Optimal Transport based on Gaussian Mixture Variational Autoencoders (PILOT-GM-VAE). PILOT-GM-VAE explores power GM-VAE estimate models describing complex distributions through efficient optimal transport algorithms for estimating distance between Mixtures. Extensive benchmarking several competing demonstrates performance in clustering, trajectory inference, correction tasks. Moreover, performed case study breast cancer atlas, where highlighted cellular molecular changes associated progression. Availability software, code, data available at https://github.com/CostaLab/PILOT-GM-VAE/tree/main

Language: Английский

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Differential neuropilin isoform expressions highlight plasticity in macrophages in the heterogenous TME through in-silico profiling

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 11, 2025

Introduction The nuanced roles of neuropilin (NRP) isoforms, NRP1 and NRP2, have attracted considerable scientific interest regarding cancer progression. Their differential expressions across various types are specific to NRP isoforms which shown in a type-dependent manner. It accounts for the different mechanisms involved, driven by co-expression gene-sets associated with overexpressed or NRP2 . on tumour-associated macrophages (TAMs) disparate markers heterogenous tumour microenvironment (TME) through their plasticity pro-tumorigenic activities. Methods Single-cell RNA sequencing (scRNA-seq) analyses were performed tumours from clear cell Renal Cell Carcinoma (ccRCC) skin cutaneous melanoma (SKCM) exhibit highest respectively. Datasets processed using established bioinformatics pipelines, including clustering algorithms, determine cellular heterogeneity quantify isoform expression within distinct macrophage populations. Using gene analysis (DEGA) alongside co-enrichment studies, we explored overexpression TAMs. Results Our revealed marked upregulation TAMs isolated ccRCC elevated SKCM-derived Both + showed an M2-like polarisation characterised immune suppression extracellular matrix degradation. Coupled previously uncharacterised - subpopulations these cancers identified DEGA, demonstrated that is angiogenesis progression VEGF signalling, while dual functionality TME-dependent regulating plasticity, invasion, metastasis highlighted. Discussion These findings underscore isoform-specific contribute TAM-mediated This study aims establish foundation future research, leading biological experiments focused derived our findings. approach can development immunomodulatory strategies targeting macrophages, tailored individual abnormal those markers, potentially offering more effective therapeutic compared broad-spectrum inhibition strategies.

Language: Английский

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Achieving high-resolution single-cell segmentation in convoluted cancer spheroids via Bayesian optimization and deep-learning

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

ABSTRACT Understanding cellular function within 3D multicellular spheroids is essential for advancing cancer research, particularly in studying cell-stromal interactions as potential targets novel drug therapies. However, accurate single-cell segmentation cultures challenging due to dense cell clustering and the impracticality of manual annotations. We present a high-throughput (HT) analysis pipeline that combines optimized wet-lab conditions, deep learning (DL)-based models, Bayesian optimization address these challenges. By using live-cell nuclear cytoplasmic dyes, we achieved clear uniform staining populations renal immune T-cell monocultures cocultures, improving detection spheroids. Our integrates image preprocessing DL models based on 3DUnet architecture, enabling robust densely packed structures. optimization, guided by custom objective function, was employed refine parameters improve quality biologically relevant criteria. The successfully segments cells under various treatments, revealing drug-induced changes not detectable bulk conventional assays. This approach has application more complex biological samples, including, organoid co-cultures, diverse integration with additional immunostaining assays, paving way detailed HT analyses responses.

Language: Английский

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Developing hypoxia and lactate metabolism-related molecular subtypes and prognostic signature for clear cell renal cell carcinoma through integrating machine learning

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 13, 2024

The microenvironment of clear cell renal carcinoma (ccRCC) is characterized by hypoxia and increased lactate production. However, the impact metabolism on ccRCC remains incompletely understood. In this study, a new molecular subtype developed based hypoxia-related genes (HRGs) metabolism-related (LMRGs), aiming to create tool that can predict survival rate, immune status, responsiveness treatment patients. We obtained RNA-seq data clinical information patients with from TCGA GEO. HRGs LMRGs are sourced Molecular Signatures Database. Integrating 10 machine learning algorithms 101 frameworks, we constructed prognostic model related metabolism. Its accuracy reliability evaluated through constructing nomograms, drawing ROC curves, validating datasets. Additionally, risk subgroups functional enrichment, tumor mutational burden (TMB), infiltration degree, checkpoint expression level. Finally, evaluate immunotherapy determine personalized drugs for specific subgroups. 85 valuable were screened out. Functional enrichment analysis shows group high-risk scores (HLMRGS) mainly involved in activation immune-related activities, while low HLMRGS more active metabolic tumor-related pathways. At same time, differences cellular states between high observed. potential determined. have novel signature integrates It expected become an effective prognosis prediction, medicine ccRCC.

Language: Английский

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Peroxidasin expression is increased in intratumoural capillaries and in proximal tubular cells adjacent to clear cell renal cell carcinoma.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Abstract Peroxidasin (PXDN), is a heme peroxidase with critical role in the crosslinking of type IV collagen, being essential for basement membrane integrity. In many cancers, PXDN overexpression has been linked processes associated poor disease outcomes, namely impairment endothelial functions, pathogenesis vascular diseases, remodelling, apoptosis, and tissue fibrosis. RCC, almost nothing so far known. this work we characterized expression tumour non-neoplastic adjacent from clear cell renal carcinoma (ccRCC) oncocytoma by immunohistochemistry. Results showed significant increase intratumoural capillaries ccRCC comparison oncocytoma, an proximal tubular epithelial cells parenchyma cases, same area oncocytomas. Overall, our results suggest, first time, that may have angiogenesis favour metastases malignity, also enrolled crosstalk between tissue, deserves further investigation. Highlights increased microvasculature comparing to oncocytoma. tubules kidney parenchyma. Is modulator microenvironment promoting angiogenesis?

Language: Английский

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