Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant tumor-associated stroma composed from pancreatic stellate cells, which play a critical role in tumor progression. Developing accurate in vitro models requires understanding the complex interactions between tumor cells and their...
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| Format: | Article |
| Language: | English |
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AIP Publishing LLC
2025-03-01
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| Series: | APL Bioengineering |
| Online Access: | http://dx.doi.org/10.1063/5.0242490 |
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| author | Soraya Hernández-Hatibi Carlos Borau Neus Martínez-Bosch Pilar Navarro José Manuel García-Aznar Pedro Enrique Guerrero |
| author_facet | Soraya Hernández-Hatibi Carlos Borau Neus Martínez-Bosch Pilar Navarro José Manuel García-Aznar Pedro Enrique Guerrero |
| author_sort | Soraya Hernández-Hatibi |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant tumor-associated stroma composed from pancreatic stellate cells, which play a critical role in tumor progression. Developing accurate in vitro models requires understanding the complex interactions between tumor cells and their microenvironment. In this study, we present a quantitative imaging-based characterization of the three dimensional (3D) self-organization of PDAC tumour spheroids using a microfluidic platform that mimics key aspects of the tumor microenvironment. Our model incorporates collagen type I hydrogels to recreate the extracellular matrix, activated human pancreatic stellate cells (HPSCs), and various tumor cell types. Advanced imaging techniques, including Lattice Lightsheet Microscopy, allowed us to analyze the 3D growth and spatial organization of the spheroids, revealing intricate biomechanical interactions. Our results indicate that alterations in matrix properties—such as stiffness, pore size, and hydraulic permeability—due to variations in collagen concentration significantly influence the growth patterns and organization of PDAC spheroids, depending on tumor subtype and epithelial–mesenchymal phenotype. Higher collagen concentrations promoted larger spheroids in epithelial-like cell lines, while mesenchymal-type cells required increased collagen for self-organization into smaller spheroids. Furthermore, coculture with HPSCs affected spheroid formation distinctly based on each PDAC cell line's genetic and phenotypic traits. HPSCs had opposing effects on epithelial-like cell lines: one cell line exhibited enhanced spheroid growth, while another showed inhibited formation, whereas mesenchymal-like spheroids showed minimal impact. These results provide insights into tumor–stroma interactions, emphasizing the importance of the cell-specific and matrix-dependent factors for advancing our understanding of PDAC progression and informing future therapeutic strategies. |
| format | Article |
| id | doaj-art-8706d5de8d44490a95d72c8d675593b4 |
| institution | OA Journals |
| issn | 2473-2877 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | AIP Publishing LLC |
| record_format | Article |
| series | APL Bioengineering |
| spelling | doaj-art-8706d5de8d44490a95d72c8d675593b42025-08-20T01:55:52ZengAIP Publishing LLCAPL Bioengineering2473-28772025-03-0191016116016116-2010.1063/5.0242490Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysisSoraya Hernández-Hatibi0Carlos Borau1Neus Martínez-Bosch2Pilar Navarro3José Manuel García-Aznar4Pedro Enrique Guerrero5Multiscale in Mechanical & Biological Engineering Research Group, Aragon Institute of Engineering Research (I3A), School of Engineering and Architecture, University of Zaragoza, Zaragoza, Aragon, SpainMultiscale in Mechanical & Biological Engineering Research Group, Aragon Institute of Engineering Research (I3A), School of Engineering and Architecture, University of Zaragoza, Zaragoza, Aragon, SpainCancer Research Program, Hospital del Mar Research Institute (HMRI), Unidad Asociada IIBB-CSIC, 08003 Barcelona, SpainCancer Research Program, Hospital del Mar Research Institute (HMRI), Unidad Asociada IIBB-CSIC, 08003 Barcelona, SpainMultiscale in Mechanical & Biological Engineering Research Group, Aragon Institute of Engineering Research (I3A), School of Engineering and Architecture, University of Zaragoza, Zaragoza, Aragon, SpainMultiscale in Mechanical & Biological Engineering Research Group, Aragon Institute of Engineering Research (I3A), School of Engineering and Architecture, University of Zaragoza, Zaragoza, Aragon, SpainPancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant tumor-associated stroma composed from pancreatic stellate cells, which play a critical role in tumor progression. Developing accurate in vitro models requires understanding the complex interactions between tumor cells and their microenvironment. In this study, we present a quantitative imaging-based characterization of the three dimensional (3D) self-organization of PDAC tumour spheroids using a microfluidic platform that mimics key aspects of the tumor microenvironment. Our model incorporates collagen type I hydrogels to recreate the extracellular matrix, activated human pancreatic stellate cells (HPSCs), and various tumor cell types. Advanced imaging techniques, including Lattice Lightsheet Microscopy, allowed us to analyze the 3D growth and spatial organization of the spheroids, revealing intricate biomechanical interactions. Our results indicate that alterations in matrix properties—such as stiffness, pore size, and hydraulic permeability—due to variations in collagen concentration significantly influence the growth patterns and organization of PDAC spheroids, depending on tumor subtype and epithelial–mesenchymal phenotype. Higher collagen concentrations promoted larger spheroids in epithelial-like cell lines, while mesenchymal-type cells required increased collagen for self-organization into smaller spheroids. Furthermore, coculture with HPSCs affected spheroid formation distinctly based on each PDAC cell line's genetic and phenotypic traits. HPSCs had opposing effects on epithelial-like cell lines: one cell line exhibited enhanced spheroid growth, while another showed inhibited formation, whereas mesenchymal-like spheroids showed minimal impact. These results provide insights into tumor–stroma interactions, emphasizing the importance of the cell-specific and matrix-dependent factors for advancing our understanding of PDAC progression and informing future therapeutic strategies.http://dx.doi.org/10.1063/5.0242490 |
| spellingShingle | Soraya Hernández-Hatibi Carlos Borau Neus Martínez-Bosch Pilar Navarro José Manuel García-Aznar Pedro Enrique Guerrero Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis APL Bioengineering |
| title | Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| title_full | Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| title_fullStr | Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| title_full_unstemmed | Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| title_short | Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| title_sort | quantitative characterization of the 3d self organization of pdac tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis |
| url | http://dx.doi.org/10.1063/5.0242490 |
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