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Updated: Sep 13, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Targeting FGFR4 abrogates HNF1A-driven metastasis in pancreatic ductal adenocarcinoma
Katherine J Crawford1,2, Kennedy S Humphrey1, Eduardo Cortes3,4
1Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, 14263, NY, USA.
Background:
We previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A-dependent phenotypes have yet to be identified.
Methods:
Transwell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells in vitro. An intrasplenic injection xenograft model was used to evaluate the impact of HNF1A knockdown and overexpression on metastatic tumor burden. Single-cell RNA sequencing (scRNA-seq), tissue microarray (TMA) data, and UMAP spatial profiling were used to identify FGFR4 as an HNF1A target gene upregulated in metastatic cells. RNAi and two FGFR4 inhibiting modalities (H3B-6527 and U3-1784) were utilized to demonstrate the efficacy of FGFR4 inhibiting agents at reducing HNF1A-driven metastasis.
Results:
Knockdown of HNF1A significantly decreases and HNF1A overexpression significantly increases PDAC cell migration and invasion. In vivo studies show that HNF1A knockdown significantly abrogates metastasis, while overexpression significantly promotes metastasis. scRNA-seq shows that FGFR4 is upregulated in metastatic PDAC cells and staining for HNF1A and FGFR4 in a PDAC TMA reveals significant correlation between HNF1A and FGFR4 in PDAC patients. Further, knockdown and inhibition of FGFR4 significantly decreases HNF1A-mediated cell migration and invasion, and blocks HNF1A-driven metastasis in vivo.
Conclusions:
These findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients.
Insights
Hepatocyte Nuclear Factor 1-Alpha (HNF1A) drives pancreatic ductal adenocarcinoma (PDAC) metastasis by increasing Fibroblast Growth Factor Receptor 4 (FGFR4). Inhibiting FGFR4 may offer a new therapeutic strategy for PDAC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Hepatocyte Nuclear Factor 1-Alpha (HNF1A) is implicated in pancreatic ductal adenocarcinoma (PDAC) oncogenesis.
- The role of HNF1A in PDAC metastasis and potential therapeutic targets remain largely unexplored.
Purpose of the Study:
- To investigate the role of HNF1A in PDAC metastasis.
- To identify and validate targeting modalities for HNF1A-driven metastatic phenotypes in PDAC.
Main Methods:
- Assessed cell migration and invasion in vitro using Transwell assays with HNF1A and FGFR4 modulation.
- Utilized an intrasplenic injection xenograft model to evaluate HNF1A's impact on metastasis.
- Employed single-cell RNA sequencing (scRNA-seq) and tissue microarray (TMA) analysis to identify FGFR4 as an HNF1A target.
- Tested RNA interference (RNAi) and FGFR4 inhibitors (H3B-6527, U3-1784) for anti-metastatic efficacy.
Main Results:
- HNF1A overexpression increased, while knockdown decreased, PDAC cell migration, invasion, and metastasis in vitro and in vivo.
- FGFR4 was identified as an HNF1A target gene upregulated in metastatic PDAC cells, with a significant correlation between HNF1A and FGFR4 expression in patients.
- Inhibition of FGFR4 reduced HNF1A-mediated migration, invasion, and metastasis.
Conclusions:
- HNF1A promotes PDAC metastasis through the upregulation of FGFR4.
- Targeting FGFR4 represents a promising therapeutic strategy to inhibit PDAC metastasis.
