Despite advances in defined culture systems, current organoid models lack programmable control of transcriptomic states beyond fixed genetic constraints or broadly specific microenvironmental conditions. Here, a bottom-up biomaterial-based platform is introduced to program cell state changes in pancreatic cancer organoids by tuning minimal adhesion cues within a synthetic matrix. A Design of Experiments framework is used to systematically model the patient-specific transcriptome-wide impact of matrix-presented adhesion cues. Focusing on epithelial-mesenchymal transition (EMT) as a proof-of-concept cellular program, a multiobjective optimization approach is applied to identify patient-specific matrix compositions that enrich EMT-associated transcriptional programs. Organoids cultured in these optimized matrices exhibit transcriptomic signatures consistent with EMT enrichment and coordinated shift in EMT-associated regulatory signatures. Secretome profiling further reveals changes in cytokines previously linked to EMT-associated inflammatory, hypoxia, and TGF-β signaling. Together, these findings demonstrate that quantitative and targeted modulation of defined adhesion cues enables programmable control of transcriptomic states in pancreatic cancer organoids.
Nadernezhad et al. (Tue,) studied this question.