Targetable programs of adult cancer are ontogenically rooted within early specified cell fate trajectories of human pluripotency

Molecular similarities between pluripotency and cancer have recently been underscored by multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, as well as tumor types that cluster based on tissue origins. Informed by these in silico studies, we now demonstrate that hPSCs serve as a cellular source to define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Functionally, chemical probes that induce hPSC germ layer specification suppressed adult cancer growth, but were restricted to tumors that correspond with shared germ layer origins. For example, metallothioneins induced mesoderm differentiation of hPSC and showed exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for oncogenic reprogramming to define a relationship between pluripotent state and human cancers that can identify covert targets for cancer therapies. Droplet-based single-cell RNA-sequencing of v1H9 transformed H9.