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Updated: Aug 25, 2026
Pancreatic Tissue-Derived Extracellular Matrix Bioink for Printing 3D Cell-Laden Pancreatic Tissue Constructs
Published on: December 13, 2019
3D-printed niche-matched GelMA-dECM bioinks rewire lipid metabolic reprogramming and chemosensitization in pancreatic
Biwen Zhu1, Tao Yang1, Mingyue Chang2
1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Research Center of Clinical Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, China.
Abstract:
Primary pancreatic ductal adenocarcinoma (PDAC) and hepatic metastases grow in anatomically distinct niches defined by organ-specific extracellular matrix (ECM) cues related to matrix composition and biomechanics such as substrate stiffness. Metabolic remodeling is a fundamental mechanism by which PDAC cells adapt to environmental stress. However, whether ECM actively imposes site-dependent metabolic liabilities remains unclear. To this end, we developed a digital light processing-printable GelMA-dECM platform incorporating decellularized pancreas- or liver-derived ECM under controlled three-dimensional culture conditions. Single-cell analysis and immunohistochemical staining of human tissues revealed a site-associated metabolic divergence, with primary pancreatic lesions enriched in cholesterol/mevalonate associated markers and liver metastases displaying stronger fatty acid synthesis signatures. Consistently, pancreas-dECM promoted HMGCS1/HMGCR-associated cholesterol and mevalonate programs in PDAC cells, whereas liver-dECM induced FASN/ACC1-associated fatty acid synthesis and lipid droplet accumulation. Increased matrix stiffness enhanced YAP activation and amplified lipid metabolic output without overriding the dECM-defined metabolic direction, indicating a mechanical amplifier role. Functionally, these matrix-encoded metabolic states predicted therapeutic vulnerability. Cholesterol/mevalonate pathway inhibition preferentially sensitized pancreas-dECM constructs and pancreatic-site tumors to gemcitabine, whereas fatty acid synthesis inhibition was more effective in liver-dECM constructs and liver-site tumors. These findings identify that organ-specific ECM defines the direction of lipid metabolic programming, whereas matrix stiffness amplifies the magnitude of this program. Together, these matrix-encoded metabolic states create site-matched therapeutic vulnerabilities in PDAC. Our study provides a potentially generalizable platform for supporting scalable microenvironment-guided modeling of site-specific tumor metabolism and therapeutic screening.
