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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133669 | GEO | 2023/05/17

REPOSITORIES: GEO

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Project description:Human pancreatic stellate cells (HPSCs) are an essential stromal component and are the mediators of pancreatic ductal adenocarcinoma (PDAC) progression. Small extracellular vesicles (sEVs) are membrane-enclosed nanoparticles released from stellate cells adjacent to the PDAC. sEVs are believed to play a key role in cell-cell communications and may play a critical role in disease progression. The role of membrane proteins of HPSC sEVs in the PDAC tumor microenvironment is unclear and to date, there has not been a quantitative proteomic comparison of sEVs from normal pancreatic stellate cells (HPaStec) and from PDAC-associated stellate cells (HPSCs). We hypothesized there would be differences in sEVs secretion and membrane protein expression between the 2 conditions that might contribute to PDAC biology. To test these hypotheses, we isolated sEVs using ultracentrifugation followed by characterization by electron microscopy and Nanoparticle Tracking Analysis. HPSCs secreted more sEVs compared to HPaStec, and these sEVs were enriched with exosomal markers, which was confirmed by Western blotting and flow cytometry. HPSC-sEVs also restore the activation of normal stellate cells. Next, we showed that intact membrane-associated proteins may be essential for sufficient uptake of stellate cell sEVs by both normal epithelial and cancer cells. Importantly, we demonstrated that stellate cells in general modulate the cellular proliferations of pancreatic cancer cells although stellate cell sEVs did not change the proliferation of cancer cells. We then compared sEV proteins isolated from HPSCs and HPaStecs cells using liquid chromatography–tandem mass spectrometry. Most of the 1,481 protein groups identified were shared with the exosome database, ExoCarta (http://exocarta.org/; curated by the Mathivanan Lab). Eighty-seven protein groups were differentially expressed (selected by 2-fold difference and adjusted P value ≤ 0.05) between HPSC and HPaStec sEVs. HPSC sEVs contained dramatically more CSE1L, a poor prognostic marker for pancreatic cancer. In conclusion, our findings using mass spectrometry–based proteomics may direct further studies to understand the biology and role of protein composition of HPSC sEVs in PDAC progression or to develop novel strategies based on delivery of exosome cargo to PDAC tumor cells.

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

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