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Targeting YAP/TEAD signaling disturbs RNA Pol II activity and enhances immunotherapy response via activated cytosolic DNA sensing pathway in gastroesophageal cancer

ABSTRACT: Gastroesophageal adenocarcinoma (GEAC) accounts for a significant global cancer burden. Our previous studies demonstrated that YAP1/TEAD are highly expressed in GEAC, and play a critical role in tumor progression, therapy resistance and metastasis. Thus, targeting YAP/TEAD signaling presents a promising therapeutic strategy. Here, we developed a novel YAP/TEAD inhibitor VT00278 based on the structure of CA3 and showed that VT00278 strongly downregulated YAP/TEAD transcriptional activity, and potently suppress tumor-promoting phenotypes, including proliferation, invasion, tumor sphere formation; induce apoptosis and inhibit tumor growth in vivo especially in radiation resistant FLO-1 XTR GEAC cells. Mechanistically, in addition to impairing YAP1/TEAD signaling, VT00278 or YAP1 depletion repressed RNA polymerase II transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptosis MCL-1 expression. More interestingly, we revealed that VT00278 strongly induced DNA damage, activated cytosolic DNA sensing pathway, upregulation of innate immune genes (e.g.INFβ) and increased PDL-1 expression. In a syngeneic mouse model, combining VT00278 with anti-PD-1 therapy synergistically inhibited tumor growth and increased CD3+ and CD8+ T cell infiltration and induced the production of INFγ from CD3 and CD8 cells in the combination treatment. These findings support VT00278 as a promising candidate for GEAC treatment, either alone or in combination with immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316491 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its coactivator protein Yki. The role of mammalian Tead proteins in growth regulation, however, remains unknown. Here we examined the role of mouse Tead proteins in growth regulation. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of Tead proteins by modulating nuclear localization of a Yki homologue, Yap, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition, and promotion of tumor formation. Growth promoting activities of various Yap mutants correlated with their Tead-coactivator activities. Tead2-VP16 and Yap regulated largely overlapping sets of genes. However, only a few of the Tead/Yapregulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap-/- embryos. Most of the previously identified Yap-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap and Tead1 varied depending on cell types. Strong nuclear accumulation of Yap and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap regulate cell proliferation differ depending on cell types, and Tead, Yap and Hippo signaling may play multiple roles in mouse embryos. We used microarrays to know the gene expression profiles regurated by Tead2-VP16, Tead2-EnR, Yap, and cell density in NIH3T3 cells. Keywords: Cell density, genetic modification Tead2-VP16-, Tead2-EnR-, Yap- and control vector-expressing cells were cultured at low or high density for RNA extraction and hybridization on Affymetrix microarrays.

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Targeting YAP/TEAD signaling disturbs RNA Pol II activity and enhances immunotherapy response via activated cytosolic DNA sensing pathway in gastroesophageal cancer

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