From Genomic Alterations to Functional Tumor Biology: Integrating Organoids and Organ-on-a-Chip in Colorectal Cancer.

Colorectal cancer (CRC) develops through the stepwise accumulation of genetic alterations, including mutations in APC, KRAS, and TP53, which drive tumor initiation and progression. Although advances in genomic profiling have significantly improved our understanding of CRC, translating these alterations into functional outcomes and therapeutic responses remains a major challenge. This limitation arises from tumor heterogeneity, context-dependent signaling, and the dynamic nature of tumor evolution. Recent advances in patient-derived organoids (PDOs) have provided a platform that preserves tumor-specific architecture and genetic features, enabling functional interrogation of drug responses. However, PDOs lack critical components of the tumor microenvironment, such as stromal, immune, and mechanical cues. Organ-on-a-chip (OoC) technologies, particularly organoid-on-a-chip systems in which PDOs are integrated into microfluidic devices, further address these limitations by recapitulating physiological conditions and multicellular interactions. In this review, we discuss the genetic evolution of CRC and highlight how emerging functional models, including PDOs and organoid-on-a-chip platforms, bridge the gap between genomic alterations and tumor behavior. We propose that integrating these platforms offers a promising framework for advancing functional precision medicine and improving our understanding of CRC biology.