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Multiplexed transcriptomics to screen drug combination and define therapeutic mechanism of action at single-cell resolution

ABSTRACT: Compared to classical drug screening, single-cell screening not only significantly enhances throughput but also provides richer transcriptional response information. In this study, we employed the high-throughput single-cell sequencing technology, snHH-seq, to screen clinical drug combinations with anti-hepatocellular carcinoma activity. Single-cell transcriptomics revealed that the combination of HHT and YM155 (HY) exhibited the most potent inhibitory effect on cellular proliferation, which was also validated through in vitro and in vivo functional assays. Mechanistically, transcription factor regulatory network analysis identified cell type-specific regulators in each subpopulation with HY treatment, and revealed that the anticancer effects primarily target apoptosis-related subpopulations. These findings provide critical insights for precision diagnosis and treatment of hepatocellular carcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291757 | GEO | 2026/05/28

REPOSITORIES: GEO

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Project description:Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and can compromise tissue perfusion. Critically, they are prone to rupture leading to frequent and uncontrolled bleeding. As a result, HHT patients experience several debilitating clinical manifestations that reduce patient quality-of-life. Most HHT patients are heterozygous for loss-of-function mutations affecting signaling through the Alk1 pathway; yet, the pathogenesis of vascular malformation (VM) in HHT patients remains unclear and there are still few treatment options and no cure. Due to the complex, three-dimensional, and multicellular nature of vascular lesions in HHT, they are traditionally studied in intact genetically-modified mouse and zebrafish models, and studies in these animals have yielded important insights into HHT disease progression. However, intact animal studies can be time-consuming and expensive, and may be difficult to translate to human patients. In this study, we take advantage of our recently developed Vascularized Micro-Organ platform to develop an in vitro fully-humanized HHT-on-a-chip microphysiological model (HHT-VMO) that recapitulates vascular lesions of HHT patients. Using a tunable IPTG-inducible ACVRL1 (Alk1)-knockdown approach, we control the timing and extent of endogenous Alk1 expression in primary human endothelial cells seeded into the HHT-VMO device. We report that Alk1-deficient EC reliably form networks with aberrant morphology that includes lesions reminiscent of both patient telangiectasias and AVMs. HHT-VMO lesions are dependent upon the timing of Alk1 knockdown and their formation is blocked by the Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor pazopanib. Lastly, we find that AVM-like lesions that form in the HHT-VMO are comprised of mixed Alk1-intact and Alk1-deficient EC suggesting cell non-autonomous effects. Taken together, we report development of a novel HHT-on-a-chip model that appears to faithfully reproduce HHT patient lesions. In the future, we hope to use this model to better understand HHT disease biology and to perform drug screening studies to identify a cure for HHT.

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Multiplexed transcriptomics to screen drug combination and define therapeutic mechanism of action at single-cell resolution

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