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Overlapping principles of embryonic and tumor biology have been described, with recent multi-omics campaigns uncovering shared molecular profiles between human pluripotent stem cells (hPSCs) and adult tumors. Here, using a chemical genomic approach, we provide biological evidence that early germ layer fate decisions of hPSCs reveal targets of human cancers. Single-cell deconstruction of hPSCs-defined subsets that share transcriptional patterns with transformed adult tissues. Chemical screening using a unique germ layer specification assay for hPSCs identified drugs that enriched for compounds that selectively suppressed the growth of patient-derived tumors corresponding exclusively to their germ layer origin. Transcriptional response of hPSCs to germ layer inducing drugs could be used to identify targets capable of regulating hPSC specification as well as inhibiting adult tumors. Our study demonstrates properties of adult tumors converge with hPSCs drug induced differentiation in a germ layer specific manner, thereby expanding our understanding of cancer stemness and pluripotency. [Display omitted] • Subsets of hPSCs share molecular properties with cancers in a tissue specific manner • Barrier genes that block specific germ layer fates of hPSCs promote pluripotency • Drugs specifying hPSC germ layer fate suppress cancers of the same germ layer alone • Applied chemical genomics of hPSCs specification reveals targets of adult cancers Orlando et al. demonstrate that transcriptional features of pluripotency are shared with tissue specific human cancers that are organized by their germ layer origin, providing a foundation to understand properties of adult tumors related to cancer stemness. [ABSTRACT FROM AUTHOR]

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers. [Display omitted] • Natural product compound (McM025044) has selective anti-neoplastic activity • McM025044 binds to SAE2 to reduce SUMOylation of intracellular proteins • SUMOylation inhibition by McM025044 impairs stem cell self-renewal • McM025044 restricts in vivo activity of SUMO-dependent leukemia initiating cells Benoit et al. screened extracts from strains of actinomycete to uncover and isolate a molecule that inhibits SUMOylation in human cancer stem cells. This natural product compound acts via biochemical targeting of a specific motif in a SUMOylation enzyme, SAE2, that regulates self-renewal of a variety of human cancer cells. [ABSTRACT FROM AUTHOR]

Summary Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction. Our study identifies Sam68 as a regulator of human CSC vulnerability. [ABSTRACT FROM AUTHOR]