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This research aims to quantitatively compare the extracellular matrix composition and spatial arrangement in human pancreatic ductal adenocarcinoma and mouse models.

April 5, 2026

Abstract 763: Bridging the translational gap: Critical TME differences between human PDAC and mouse models.

Key Points

This research aims to quantitatively compare the extracellular matrix composition and spatial arrangement in human pancreatic ductal adenocarcinoma and mouse models.
Tissue sections from human PDAC and a mouse model were analyzed.
Staining techniques utilized included H&E, Picrosirius Red, and Alcian Blue.
Quantitative analyses were performed using AI/ML imaging tools and spatial metrics were evaluated.
Principal component analysis was conducted to assess differences in ECM characteristics.
Human PDAC had a balanced ECM composition (collagen=0.16, HA=0.18), while mouse tumors showed collagen depletion (collagen=0.04, HA=0.26).
Edge mapping indicated a 4-fold increase in peripheral collagen in mouse tumors compared to human PDAC.
Human tumors exhibited greater spatial disorder and entropy (entropy scores above 8) compared to mouse tumors, which were more ordered (entropy around 7.8).
Principal component analysis distinctly separated human samples from mouse samples based on collagen-HA balance and textural analysis.

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) develops within a dense, heterogeneous tumor microenvironment (TME) in which collagen and hyaluronic acid (HA) shape tissue architecture, biomechanics, and therapeutic response. Although mouse PDAC models are widely used, their ability to recapitulate human extracellular matrix (ECM) organization remains uncertain. This study aimed to quantitatively compare ECM composition and spatial topology in human PDAC versus a commonly used mouse model. Methods: Tissue sections from primary human PDAC (n=6) and a syngeneic PDAC mouse model (n=3) were stained with H HA=0.18±0.04), whereas mouse tumors showed HA enrichment and collagen depletion (collagen=0.04±0.002; HA=0.26±0.09). Edge mapping revealed proportionate collagen and HA in human samples (edge ratio=0.9±0.46) but 4-fold peripheral collagen enrichment in mouse tumors (edge ratio=4.3±1.3). Human tumors demonstrated higher entropy (collagen=8.1±0.2; HA=7.9±0.2) and substantial HA autocorrelation (Moran’s I=0.58±0.22; 0.60±0.42), reflecting heterogeneous, regionally clustered desmoplasia. Mouse tumors displayed reduced entropy (∼7.8) and lower Moran’s I (0.32±0.05; 0.17±0.01), indicative of ordered, capsule-like ECM organization. Principal component analysis distinctly segregated species: PC1 (42%) collagen-HA balance, with human samples scoring positive and mouse samples negative; PC2 (21%) textural heterogeneity versus edge-localized order. Conclusions: These findings show that the murine PDAC model fails to reproduce the balanced collagen-HA composition and spatially disordered desmoplasia of human PDAC, instead forming an HA-rich, collagen-depleted core encased in an ordered collagen capsule with markedly lower stromal entropy and autocorrelation. These findings highlight the limitations of mouse models, particularly subcutaneous tumor models, and underscores the need for human-relevant new approach methods (NAMs) for translational therapeutic studies. Citation Format: Rachael Guenter, Libby A. Boykin, Khidr Kishan K. Budhwani, Brahma Mubarak K. Budhwani, Chelsea L. Crawford, J. Bart Rose, Karim I. Budhwani. Bridging the translational gap: Critical TME differences between human PDAC and mouse models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 763.

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Abstract 763: Bridging the translational gap: Critical TME differences between human PDAC and mouse models.

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