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Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

ABSTRACT: Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

SUBMITTER: Wang Y

PROVIDER: S-EPMC11012314 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

Wang Yishu Y Chen Xiaomin X Tang Ningjun N Guo Mengyao M Ai Dongmei D

International journal of molecular sciences 20240408 7

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cell ...[more]

PMID: 38612943

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Project description:For clear cell renal cell carcinoma (ccRCC) risk-dependent diagnostic and therapeutic algorithms are routinely implemented in clinical practice. Artificial intelligence-based image analysis has the potential to improve outcome prediction and thereby risk stratification. Thus, we investigated whether a convolutional neural network (CNN) can extract relevant image features from a representative hematoxylin and eosin-stained slide to predict 5-year overall survival (5y-OS) in ccRCC. The CNN was trained to predict 5y-OS in a binary manner using slides from TCGA and validated using an independent in-house cohort. Multivariable logistic regression was used to combine of the CNNs prediction and clinicopathological parameters. A mean balanced accuracy of 72.0% (standard deviation [SD] = 7.9%), sensitivity of 72.4% (SD = 10.6%), specificity of 71.7% (SD = 11.9%) and area under receiver operating characteristics curve (AUROC) of 0.75 (SD = 0.07) was achieved on the TCGA training set (n = 254 patients / WSIs) using 10-fold cross-validation. On the external validation cohort (n = 99 patients / WSIs), mean accuracy, sensitivity, specificity and AUROC were 65.5% (95%-confidence interval [CI]: 62.9-68.1%), 86.2% (95%-CI: 81.8-90.5%), 44.9% (95%-CI: 40.2-49.6%), and 0.70 (95%-CI: 0.69-0.71). A multivariable model including age, tumor stage and metastasis yielded an AUROC of 0.75 on the TCGA cohort. The inclusion of the CNN-based classification (Odds ratio = 4.86, 95%-CI: 2.70-8.75, p < 0.01) raised the AUROC to 0.81. On the validation cohort, both models showed an AUROC of 0.88. In univariable Cox regression, the CNN showed a hazard ratio of 3.69 (95%-CI: 2.60-5.23, p < 0.01) on TCGA and 2.13 (95%-CI: 0.92-4.94, p = 0.08) on external validation. The results demonstrate that the CNN's image-based prediction of survival is promising and thus this widely applicable technique should be further investigated with the aim of improving existing risk stratification in ccRCC.

Project description:Backgroundvon Hippel-Lindau syndrome (VHL) is an autosomal dominant hereditary syndrome with an increased predisposition of developing numerous cysts and tumors, almost exclusively clear cell renal cell carcinoma (ccRCC). Considering the lifelong surveillance in such patients to monitor the disease, patients with VHL are preferentially imaged using MRI to eliminate radiation exposure.PurposeSegmentation of kidney and tumor structures on MRI in VHL patients is useful in lesion characterization (e.g., cyst vs. tumor), volumetric lesion analysis, and tumor growth prediction. However, automated tasks such as ccRCC segmentation on MRI is sparsely studied. We develop segmentation methodology for ccRCC on T1 weighted precontrast, corticomedullary, nephrogenic, and excretory contrast phase MRI.MethodsWe applied a new neural network approache using a novel differentiable decision forest, called hinge forest (HF), to segment kidney parenchyma, cyst, and ccRCC tumors in 117 images from 115 patients. This data set represented an unprecedented 504 ccRCCs with 1171 cystic lesions obtained at five different MRI scanners. The HF architecture was compared with U-Net on 10 randomized splits with 75% used for training and 25% used for testing. Both methods were trained with Adam using default parameters ( α=0.001,β1=0.9,β2=0.999$\alpha = 0.001,\ \beta _1 = 0.9,\ \beta _2 = 0.999$ ) over 1000 epochs. We further demonstrated some interpretability of our HF method by exploiting decision tree structure.ResultsThe HF achieved an average kidney, cyst, and tumor Dice similarity coefficient (DSC) of 0.75 ± 0.03, 0.44 ± 0.05, 0.53 ± 0.04, respectively, while U-Net achieved an average kidney, cyst, and tumor DSC of 0.78 ± 0.02, 0.41 ± 0.04, 0.46 ± 0.05, respectively. The HF significantly outperformed U-Net on tumors while U-Net significantly outperformed HF when segmenting kidney parenchymas ( α<0.01$\alpha < 0.01$ ).ConclusionsFor the task of ccRCC segmentation, the HF can offer better segmentation performance compared to the traditional U-Net architecture. The leaf maps can glean hints about deep learning features that might prove to be useful in other automated tasks such as tumor characterization.

Dataset Information

Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

Publications

Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

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