Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. SIGNIFICANCE: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.

The ELAVL3/MYCN positive feedback loop provides a therapeutic target for neuroendocrine prostate cancer.

Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.

Serum extracellular vesicles derived hsa-miR-320d as an indicator for progression of clear cell renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent malignancy with a rising incidence in developing countries. Clear cell renal cell carcinoma (ccRCC) constitutes 70% of RCC cases and is prone to metastasis and recurrence, yet lacks a liquid biomarker for surveillance. Extracellular vesicles (EVs) have shown promise as biomarkers in various malignancies. In this study, we investigated the potential of serum EV-derived miRNAs as a biomarker for ccRCC metastasis and recurrence. MATERIALS AND METHODS: Patients diagnosed with ccRCC between 2017 and 2020 were recruited in this study. In the discovery phase, high throughput small RNA sequencing was used to analyze RNA extracted from serum EVs derived from localized ccRCC (LccRCC) and advanced ccRCC (AccRCC). In the validation phase, qPCR was employed for quantitative detection of candidate biomarkers. Migration and invasion assays were performed on ccRCC cell line OSRC2. RESULTS: Serum EVs derived hsa-miR-320d was significantly up-regulated in patients with AccRCC than in patients with LccRCC (p < 0.01). In addition, Serum EVs derived hsa-miR-320d was also significantly up-regulated in patients who experienced recurrence or metastasis (p < 0.01). Besides, hsa-miR-320d enhances the pro-metastatic phenotype of ccRCC cells in vitro. CONCLUSIONS: Serum EVs derived hsa-miR-320d as a liquid biomarker exhibits significant potential for identifying the recurrence or metastasis of ccRCC, as well as hsa-miR-320d promotes ccRCC cells migration and invasion.

Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma.

To investigate the role of patient-derived organoid (PDO) model in the precision medicine of advanced clear cell renal cell carcinoma (ccRCC), we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022. The seven patients were diagnosed with advanced ccRCC with or without remote metastasis. Cytoreductive and radical nephrectomy was performed respectively. To predict the response to immunotherapy and provide personalized medicine recommendation, a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed. Hematoxylin and eosin (H&E) staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor. Immunofluorescence staining identified that CD3+ T cells, SMA+ cancer associated fibroblasts, and CD31+ endothelial cells were preserved in PDO models. Fluorescence activated cell sorter (FACS) revealed an evidently increased ratio of CD8+/CD4+ T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4. The results showed that toripalimab is able to rescue the excessive death of CD8+ T cells by critically reversing the immune exhaustion state of ccRCC in PDO model. This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC.

Integration of Tumor Microenvironment in Patient-Derived Organoid Models Help Define Precision Medicine of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is a common urological tumor, with a poor prognosis, as the result of insensitivity to chemotherapy and radiotherapy. About 20%-30% of patients with RCC have metastasis at the first diagnosis, so only systemic treatment is possible. Due to the heterogeneity of renal tumors, responses to drugs differ from person to person. Consequently, patient-derived organoid, highly recapitulating tumor heterogeneity, becomes a promising model for high-throughput ex vivo drug screening and thus guides the drug choice of patients with RCC. Systemic treatment of RCC mainly targets the tumor microenvironment, including neovasculature and immune cells. We reviewed several methods with which patient-derived organoid models mimic the heterogeneity of not only tumor epithelium but also the tumor microenvironment. We further discuss some new aspects of the development of patient-derived organoids, preserving in vivo conditions in patients with RCC.