Abstract 243: FLT4, a novel regulator of renal cell carcinoma progression
Bibliographic record
Abstract
Abstract Background: Clear Cell Renal Cell Carcinoma (ccRCC) is one of the ten most frequently diagnosed malignancies worldwide and constitutes 2-3% of all adult cancers. Disruption of p53 function, a critical tumor suppressor, plays a pivotal role in cancer development and resistance to chemotherapy. While p53 gene mutations are rare in ccRCC, these tumors often resist DNA-damage- based therapies, suggesting alternative mechanisms suppressing wild-type p53 in ccRCC. Therefore, reactivating this pathway represents a potential therapeutic strategy. p53 is tightly regulated by MDM2 and MDMX which are frequently elevated in ccRCC patients. However, the molecular mechanisms underlying MDM2/MDMX-mediated p53 regulation in ccRCC remain unclear. Our study identified the Receptor Tyrosine Kinase FLT4 as a novel regulator of MDM2/MDMX and p53 activity. Notably, both FLT4 and its ligand, VEGFC, are overexpressed in ccRCC patients. Hypothesis: We propose that FLT4 activation increases the stability of the MDM2/MDMX complex, resulting in p53 inactivation and promoting ccRCC tumorigenesis. Methods: 1) We analyzed Bulk and single cell RNAseq data of ccRCC patients from the Cancer Genome Atlas (TCGA) to assess the expression of FLT4 and VEGFC. 2) The ccRCC cell lines ACHN and Caki-2 were used for in vitro experiments, including VEGFC treatment for functional assays (proliferation, migration, and survival) and MDM2/MDMX/p53 protein analysis. 3) ACHN and Caki-2 cells were transduced with Luciferase and FLT4 and injected into immunodeficient NOD/SCID mice to study tumor development and metastasis using In vivo Imaging System (IVIS). Results: FLT4 and VEGFC are overexpressed in ccRCC patients and correlate with cancer progression and poor survival. In addition, FLT4 activation promotes proliferation and migration both in vitro and in vivo and reduces the chemosensitivity of ccRCC cells mainly through the modulation of p53 levels. Mechanistically, FLT4 activation decreases p53 stability and activity by increasing MDM2/MDMX levels through post-translational modifications. Conclusion: Aberrant FLT4 signaling drives ccRCC progression by suppressing p53 through the upregulation of its negative regulators MDM2 and MDMX. These findings highlight FLT4 as a potential target for restoring p53 activity and improving ccRCC outcomes. Citation Format: Djazia Haferssas, Nathalie Henley, Jonatan Barrera Chimal, Casimiro Gerarduzzi. FLT4, a novel regulator of renal cell carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 243.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".