Abel, E. V. | bioRxiv Science

bioRxiv2025

Targeting FGFR4 Abrogates HNF1A-driven Metastasis in Pancreatic Ductal Adenocarcinoma

PurposeWe 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. Experimental DesignTranswell 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, 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. ResultsKnockdown 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. Single-cell RNAseq 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. ConclusionsThese findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients. Translational RelevancePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, made even more devastating when metastases overwhelm major organs. The vast majority of PDAC patients either present with metastases or will relapse with recurrent metastatic PDAC after primary tumor resection. Unfortunately, toxic and largely ineffective chemotherapies are currently the only approved treatment options for these patients and therefore there exists a critical and unmet clinical need for targeted therapies against pro-metastatic pathways in PDAC. In the current study, we identify HNF1A as an oncogenic transcription factor that drives metastasis in PDAC, and it does so through upregulation of the receptor tyrosine kinase FGFR4. Importantly, FGFR4 is a targetable vulnerability and treatment with an FGFR4 blocking antibody reduces HNF1A-driven metastasis. These findings suggest that FGFR4 inhibitors could be an efficacious treatment for PDAC patients for the prevention or delay of metastatic tumor development.

cancer biology↗

bioRxiv2023

Pharmacologically targeting KRASG12D in PDAC models:tumor cell intrinsic and extrinsic impact

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here we assessed the cellular response to pharmacological KRAS inhibition, which target the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of KRASG12D allele, with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR screens identify new drivers for enhanced therapeutic response that regulate focal adhesion and signaling cascades, which were confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures and in vivo PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition elicits potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133 activates interferon-{gamma} signaling and induces antigen presentation that modulate the tumor microenvironment. Further investigation on the immunological response using single cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8+ T-cells. Thus, both tumor cell intrinsic and extrinsic events contribute to response and credential KRASG12D inhibition as promising strategy for a large percentage of PDAC tumors.

cancer biology↗