ORCID

https://orcid.org/0009-0001-9457-6099

Keywords

FGF19, FGFR4, colorectal cancer, breast cancer, therapeutic resistance, serum biomarker

Subject Categories

Medical Molecular Biology

Abstract

The fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) signaling pathway regulates hepatic metabolism, bile acid (BA) synthesis, and hepatocyte proliferation. This signaling axis also is implicated in promoting tumor progression, therapeutic resistance, and metastasis in certain cancers.

In colorectal cancer (CRC) there is a critical need for non-invasive biomarkers for disease detection and monitoring. We identified FGF19 as a candidate CRC serum marker through meta-transcriptomics and found FGF19 to be expressed and secreted by CRC cell lines. Tumor-derived FGF19 was detectable in mouse serum at levels correlating with tumor volume in a subcutaneous xenograft model. RNA sequencing of hepatic tissue further revealed that CRC secreted FGF19 suppressed BA synthesis, uncovering previously undescribed enteroendocrine effects of tumor-derived FGF19 on liver physiology and cholesterol metabolism. The association of serum FGF19 with tumor volume supports its utility as a minimally invasive marker that could increase screening compliance and improve disease monitoring.

Given that FGF19 signals through FGFR4, we investigated FGFR4 in breast cancer (BC). FGFR4 is a molecular hallmark of the HER2-enriched (HER2E) BC subtype. A main challenge for this subtype is acquired resistance to anti-HER2 therapies which limits treatment options. To address this, we employed BLU554 as an FGFR4 inhibitor in HER2E BC cells resistant to lapatinib (LapR). Dual therapy synergistically reduced cell viability and induced apoptosis by suppression of pro-survival and proliferation pathways. These findings identify FGFR4 as a mediator of anti-HER2 resistance and support combined FGFR4/HER2 targeting as a strategy to improve therapeutic response in resistant disease.

Collectively, this work defines novel and context-specific roles for the FGF19–FGFR4 axis in cancer, establishing FGF19 as a metabolically active CRC serum marker and FGFR4 as a therapeutic vulnerability in resistant BC.

Completion Date

2026

Semester

Summer

Committee Chair

Altomare, Deborah

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Document Type

Dissertation

Language

English

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