Tumor Heterogeneity in VHL Drives Metastasis in Clear Cell Renal Cell Carcinoma

Hu, Junhui; Tan, Ping-Heng; Ishihara, Moe; Bayley, Nicholas; Schokrpur, Shiruyeh; Reynoso, Jeremy; Jat, Parmjit; Snick, Jacques Van; Knudsen, Beatrice S.; Chin, Arnold I.; Prins, Robert M.; Graeber, Thomas G.; Xu, Hua; Wu, Lily

doi:10.21203/rs.3.rs-846239/v1

Cited by 6 publications

(6 citation statements)

References 66 publications

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“…1D), we compared mRNA expressions between groups and observed that patients with chromosome 3 loss and chromosome 8 gain indeed have statistically lower expression of VHL. As reported in numerous scientific articles (19,27,28), the implication of VHL in regulating HIF levels was evident, with both HIF-1 alpha and EPAS1 (HIF-2 alpha) levels drastically increased in these patients. This led to an increase in a classical endothelial marker and EPAS1 target, VE-cadherin.…”

Section: Discussionmentioning

confidence: 56%

Primordial Vasculogenic Mimicry Formation in Uveal Melanoma

Bellido,

Chacon-Barrado,

Olmedo-Pelayo

et al. 2024

Preprint

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Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and where Vasculogenic Mimicry (VM) was first described. VM allows aggressive cancer cells to form blood networks independently, complicating treatment to patients from different tumor origin. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK) enhance the Kaiso/β-catenin/TCF-4 associates with VE-cadherin, enhancing VM. Disabling FAK prevents Y658 phosphorylation, causing VE-Cadherin/β-catenin dissociation and β-catenin degradation, reducing TCF-4-dependent gene transcription. Combined FAK inhibitor PF-271 and bevacizumab treatment significantly reduces tumor growth. Recently, an allosteric HIF2 inhibitor (Belzutifan) was FDA approved for VHL-associated ccRCCs and is in phase III testing for sporadic ccRCCs. In this original article, we decipher the primary causes of VM formation in UM patients with chromosome 3 loss and chromosome 8 gain, with VHL, BAP1, and FAK playing significant roles in initiating VM and consequently causing metastasis-related death in these patients. Using a combination of Belzutifan and FAKi, we observe a significant reduction in xenograft UM cells. In conclusion, we propose the combination of HIF-2i and FAKi as a prophylactic measure and for UM patients with metastasis, as this prevents VM formation and the hypoxic conditions generated by the chromosome 3 loss 8 gain.

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Section: Discussionmentioning

confidence: 56%

Primordial Vasculogenic Mimicry Formation in Uveal Melanoma

Bellido,

Chacon-Barrado,

Olmedo-Pelayo

et al. 2024

Preprint

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“…RL-GenRisk successfully identified known ccRCC risk genes. Among the top 20 ccRCC risk genes identified by RL-GenRisk, 10 genes are listed in the IntOGen database and recognized as ccRCC risk genes in prior research, including VHL [66, 67], PBRM1 [68, 69], SETD2 [70, 71], BAP1 [72, 73], MTOR [74, 75], ATM [76, 77], SPEN [78], and PTEN [79, 80]. This demonstrates that RL-GenRisk can effectively identify ccRCC risk genes.…”

Section: Discussionmentioning

confidence: 99%

Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning

Lu,

Zheng,

Hao

et al. 2024

Preprint

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Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. However, our understanding of ccRCC risk genes remains limited. This gap in knowledge poses significant challenges to the effective diagnosis and treatment of ccRCC. To address this problem, we propose a deep reinforcement learning-based computational approach named RL-GenRisk to identify ccRCC risk genes. Distinct from traditional supervised models, RL-GenRisk frames the identification of ccRCC risk genes as a Markov decision process, combining the graph convolutional network and Deep Q-Network for risk gene identification. Moreover, a well-designed data-driven reward is proposed for mitigating the lim-itation of scant known risk genes. The evaluation demonstrates that RL-GenRisk outperforms existing methods in ccRCC risk gene identification. Additionally, RL-GenRisk identifies ten novel ccRCC risk genes. We successfully validated epidermal growth factor receptor (EGFR), corroborated through independent datasets and biological experimentation. This approach may also be used for other diseases in the future.

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“…Compared with patients with kidney cancer, no esophageal perforation was detected. Treatment for kidney cancer typically excludes the management of the esophageal site, except in cases where kidney cancer has metastasized, affecting specific areas such as the lungs, which may directly impact the esophagus through lung cancer 27 . As a result of the unique location of the tumor, thyroid cancer can directly impact the natural condition and functioning of the esophagus.…”

Section: Discussionmentioning

confidence: 99%

Disproportionality Analysis of Lenvatinib‐Caused Gastrointestinal Perforation in Cancer Patients: A Pharmacovigilance Analysis Based on the US Food and Drug Administration Adverse Event Reporting System

Zhou

Wei

Zheng

et al. 2023

The Journal of Clinical Pharma

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Lenvatinib is a medication that targets multiple tyrosine kinases and is commonly used to treat various types of cancer. With its frequent usage, monitoring and assessing its potential adverse effects has become crucial. This study utilizes the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to analyze the possible link between lenvatinib and gastrointestinal perforation. FAERS was used to analyze adverse drug reactions (ADRs) linked with lenvatinib from the first quarter of 2015 to the last quarter of 2022. The association between lenvatinib and gastrointestinal perforation was evaluated using disproportionality analyses. This study included 464 patients who developed gastrointestinal perforation after using lenvatinib. Perforation involved the entire digestive tract, with the colon among the most commonly affected perforation sites, and previously undetected esophageal perforation was frequently observed. Patients with uterine and liver cancer were at a higher risk of developing gastrointestinal perforation; patients with liver cancer experienced a shorter onset time, whereas patients with endometrial cancer had a slower onset time. Middle‐aged and elderly patients exhibited a higher propensity for developing gastrointestinal perforation than younger adults. Patients with gastrointestinal perforation were found to have a significantly higher mortality rate than patients without gastrointestinal perforation. This study has identified several gastrointestinal perforation events not included in the drug instructions. It has also described the perforation site and clinical characteristics based on various types of cancer. These results could provide valuable insights for developing safer and more effective regulatory strategies concerning the use of lenvatinib.

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Tumor Heterogeneity in VHL Drives Metastasis in Clear Cell Renal Cell Carcinoma

Cited by 6 publications

References 66 publications

Primordial Vasculogenic Mimicry Formation in Uveal Melanoma

Primordial Vasculogenic Mimicry Formation in Uveal Melanoma

Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning

Disproportionality Analysis of Lenvatinib‐Caused Gastrointestinal Perforation in Cancer Patients: A Pharmacovigilance Analysis Based on the US Food and Drug Administration Adverse Event Reporting System

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