Authors
Luan, Q., Rahnama, A., Pulido, I., Raspini, M., Zhou, J., Shimamura, T., Papautsky, I.
Abstract
Tumor models that recapitulate 3D architecture are essential for understanding how cellular organization and microenvironmental interactions govern therapeutic response in human cancers. Here, we developed a microfluidic microphysiological system that enables controlled and scalable culture and drug testing of non-small cell lung cancer spheroids and patient-derived organoids. The platform integrated U-shaped microwells with dual-channel loading to support de novo spheroid formation, efficient trapping of pre-formed spheroids, and loading of intact organoids with reduced size heterogeneity. Tumor spheroids and organoids maintained high viability and structural integrity during long-term on-chip culture, and constrained microscale confinement produced ellipsoidal geometries that deviate from idealized spherical assumptions. Baseline genotype-dependent responses to KRAS G12C and EGFR inhibitors were preserved across agarose and microfluidic formats, establishing a validated reference state. Building on this baseline, fibroblast- and endothelial-derived cues consistently attenuated responses to targeted therapies across conditioned media, mixed co-culture, and spatially organized configurations. Resistance phenotypes converged on a dominant role for paracrine signaling, while increasing architectural complexity primarily enhanced morphological fidelity rather than altering therapeutic response. These findings establish a microphysiological framework that decouples tumor-intrinsic drug sensitivity from microenvironment-mediated modulation, enabling the systematic evaluation of paracrine resistance mechanisms in NSCLC.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 20 Jun 2026.
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