Abstract 2698: Altered collagen morphology in pancreatic cancer treated with the iRGD tumor-penetrating peptide

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, collagen-rich stroma that impedes drug delivery. We investigated how iRGD-mediated nanoparticle delivery modifies collagen architecture using humanized mouse models. Computational analysis of Picro-Sirius Red-stained whole-slide images (WSIs) using curvelet transform-based fiber extraction method (CT-FIRE) was performed to quantitatively examine changes in collagen features, thereby understanding treatment-induced alterations in the tumor microenvironment (TME). Methods: Humanized PDAC mice were prepared with either the human PANC-1 cell line or 0779 primary human PDAC cells and treated with or without iRGD monotherapy for two months (n=12). Primary tumors were sectioned and stained with Picro-Sirius Red to visualize collagen structures. WSIs of Picro-Sirius Red-stained tissues were analyzed with CT-FIRE to extract six morphological features of collagen, including average fiber length, waviness, and density to capture structural changes. WSIs were divided into 256×256 pixel tiles with consistent sampling through bootstrapping, followed by permutation testing for statistical validation (1,000 permutations, p<0.01). Results: Computational analysis revealed significant iRGD-induced collagen remodeling with quantifiable changes in key structural and morphological features. Permutation testing showed that, compared to controls, average fiber length decreased by 3.27% (p<0.01), waviness reduced by 3.25% (p<0.01), and density diminished by 36.3% (p<0.01), compared to controls. The structural changes were more notable in 0779-derived tumors compared to PANC-1, with reductions in average fiber length (1.03%, p<0.01), waviness (8.78%, p<0.01), and collagen density (24.27%, p<0.01), demonstrating cell-line dependent stromal remodeling. Conclusions: Our findings suggest that long-term iRGD therapy alters collagen morphology in PDAC. Further investigation is warranted to understand how these alterations contribute to enhanced penetration of drugs and immune cells observed in iRGD-treated PDAC tumors. The observed cell-line dependent variations in stromal remodeling suggest tumor heterogeneity influences treatment response, highlighting the potential for personalized therapeutic approaches in stromal-rich tumors like PDAC. Citation Format: Yoon Ho Choi, Minji Kim, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Seock-Jin Chung, Kazuki N. Sugahara, Tae Hyun Hwang. Altered collagen morphology in pancreatic cancer treated with the iRGD tumor-penetrating peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2698.