Abstract A015 FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor
Bibliographic record
Abstract
Abstract Favorable Histology Wilms tumor (FHWT) is the most common pediatric kidney cancer and those with relapsed FHWT continue to have poor prognoses. A challenge in the field of FHWT research is the lack of faithful preclinical in vitro models for both primary and relapsed tumors. This prevents us from understanding the biology of FHWT and introducing new targeted therapies into FHWT clinical trials. We recently established 10 FHWT cell lines, including one from a relapsed case, which faithfully recapitulated the genome and transcriptome of the primary tumor. However, challenges persist in maintaining the long-term growth of these cell lines, limiting our insight into the functional study of FHWT. Through comparison of the transcriptome of the FHWT primary tumor samples to their respective cell lines, we identified upregulation of fibroblast growth factor 8 (FGF8) expression in primary tumors. We then performed functional genomics to study the role of FGF8 in FHWT. We found that the splice variants, FGF8b or FGF8f, are required for the maintenance of FHWT cells. Re-introducing these two splice variants using either exogenous addition or endogenous overexpression led to increased viability and passaging of FHWT cell line models by an average of 100% and 30%, respectively. Further, we found that overexpressing FGF8b or FGF8f led to increased clonogenicity and invasion in vitro and led to tumor formation in vivo. Our mechanistic studies suggest that FGF8 drives a stemness and proliferation program through a non-canonical KRAS/MAPK pathway: FGF8b and FGF8f overexpression activates MEK1/2 without activating Erk1/2 while still promoting ETV1 and ETV4, leading to increased cell proliferation. Abrogation of MAPK pathway in vitro using MEK inhibitors led to decreased viability in cells overexpressing FGF8b and FGF8f. Together, our study highlights the oncogenic effect of FGF8 in FHWT and links FHWT to an unexpected non-canonical MAPK pathway. Citation Format: Yongdong Su, Katie T. Skinner, Garrett W. Cooper, Sumin Kang, Hong Yin, Jason T. Yustein, Andrew L. Hong. FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A015.
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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) | 0.002 | 0.000 |
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".