Organoids and AI Join Forces to Trick Cancer’s Toughest Cells—the Ones That Spread, Resist, and Relapse—Into Dying

To improve precision in disease modeling, the HUMANOID^TM Center of Research Excellence (CoRE) uses precise computational tools to rigorously vet organoid models. In this webinar, we highlight the combined use of ATCC’s colorectal cancer (CRCs) organoids with an unbiased network-based approach to track, differentiate, and selectively target cancer stem cells (CSCs). We built a transcriptomic network to identify therapeutic perturbations that can reinstate the expression of CDX2, a transcription factor whose loss identifies poorly differentiated (CSC-enriched) CRCs and whose reinstatement is predicted to reduce the risk of death/relapse by 50%. Here, the top candidate target predictably shifts the network, induces CDX2 and crypt differentiation, and shows selective cytotoxicity towards CDX2-negative models. A 50-gene signature of therapeutic response shows that CDX2-reinstatement therapy is expected to translate into a ∼50% reduction in the risk of mortality/recurrence. These results indicate that CDX2-reinstatement selectively triggers differentiation and death of colorectal CSCs, thereby demonstrating that our network-guided approach identifies a first-in-class differentiation therapy agent in solid tumors.

Key takeaways

• We use human-derived organoid models that retain both the genetic and epigenetic aspects of the diseased cell states.
• Human-derived disease models enable the discovery of novel biology and the validation of biomarkers and therapeutic targets in ‘Phase 0’ trials.
• This ‘Phase 0’ approach is designed to improve both precision and personalization, thereby closing the translational gap in modern medicine.