Work

Therapy-Dependent Modulation of Fibroblast Activation Protein Expression in Pancreatic Ductal Adenocarcinoma: Implications for FAP-Targeted Radiopharmaceutical Therapy

Year: 2026

Type: article

Abstract: Background/Objectives: This study investigated the treatment-dependent dynamics of FAP expression in human pancreatic ductal adenocarcinoma (PDAC) and preclinical xenografts to inform optimal patient selection and timing for fibroblast activation protein (FAP)-targeted theranostics. Methods: FAP expression was assessed by immunofluorescence (IF) staining of human PDAC samples, including treatment-naïve (n = 7), chemotherapy- and chemoradiotherapy-responsive tumors (n = 8), and adjacent pancreatic tissues (n = 4), and validated at the transcript level by RNA sequencing (seq). The institutional bulk RNA-seq data were integrated with a published PDAC cohort from the Human Tumor Atlas Network, together including treatment-naïve (n = 54), treatment-sensitive (n = 9), partially resistant (n = 14), treatment-resistant (n = 56), and adjacent pancreas (n = 4) tissue samples. In parallel, dynamic FAP expression was evaluated in FOLFIRINOX-sensitive PANC-1 and FOLFIRINOX-resistant SU8686 PDAC xenografts by IF. Results: IF quantification showed increased FAP expression in treatment-sensitive human PDAC compared to treatment-naïve tumors and adjacent pancreas. Integrated transcriptomic analysis revealed therapy-dependent FAP modulation, with higher FAP transcripts in treatment-sensitive tumors compared to resistant and naïve tumors. Cell-type deconvolution showed reduced inflammatory cancer-associated fibroblasts in treatment-sensitive tumors and enrichment in resistant ones, while myofibroblastic cancer-associated fibroblasts remained consistently abundant across all treatment states. In xenografts, FAP expression remained unchanged in PANC-1 tumors throughout treatment, whereas SU8686 tumors showed transient FAP upregulation on days 9 and 15 that did not persist. Conclusions: Findings highlight FAP as an abundant and actionable theranostic biomarker for PDAC patients across treatment states. Mouse models of human PDAC may not reliably recapitulate FAP changes in humans. These findings provide a framework for treatment-informed patient selection for FAP-directed theranostics in PDAC.

Source: Pharmaceutics

DOI: 10.3390/pharmaceutics18111361