Programmable Living Units for Emulating Pancreatic Tumor‐Stroma Interplay

Bioengineering close‐to‐native in vitro models that emulate tumors bioarchitecture and microenvironment is highly appreciable for improving disease modeling toolboxes. Herein, pancreatic cancer living units—so termed cancer‐on‐a‐bead models—are generated. Such user‐programmable in vitro platforms exhibit biomimetic multicompartmentalization and tunable integration of cancer associated stromal elements. These stratified units can be rapidly assembled in‐air, exhibit reproducible morphological features, tunable size, and recapitulate spatially resolved tumor‐stroma extracellular matrix (ECM) niches. Compartmentalization of pancreatic cancer and stromal cells in well‐defined ECM microenvironments stimulates the secretion of key biomolecular effectors including transforming growth factor β and Interleukin 1‐β, closely emulating the signatures of human pancreatic tumors. Cancer‐on‐a‐bead models also display increased drug resistance to chemotherapeutics when compared to their reductionistic counterparts, reinforcing the importance to differentially model ECM components inclusion and their spatial stratification as observed in vivo. Beyond providing a universal technology that enables spatial modularity in tumor‐stroma elements bioengineering, a scalable, in‐air fabrication of ECM‐tunable 3D platforms that can be leveraged for recapitulating differential matrix composition occurring in other human neoplasias is provided here. A methodology using superhydrophobic surfaces is proposed here to establish 3D cancer‐on‐a‐bead models. Such stratified living models aim to recapitulate key pancreatic ductal adenocarcinoma features including its differential spatial organization of tumor and stromal components by tuning cells and extracellular matrix compartments independently. This strategy opens new avenues for large‐scale fabrication of stratified living units compatible with high‐throughput /high‐content analysis.