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Several colorectal cancer patient derived tumor organoid RNAseq data

ABSTRACT: Acquired drug resistance is a major challenge for cancer therapy and the leading cause of cancer mortality. However, the mechanisms of drug resistance are diverse and the strategy to specifically target drug resistant cancer cells remains an unmet clinical issue. We establisheda32 colorectal cancer (CRC) PDO biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies34 revealed that chemo-resistant PDOs exhibited elevated expression of LGR4 and activationof the35 Wnt signaling pathway. Further, we performed antibody screening against LGR4 and selecteda36 monoclonal antibody (LGR4-mAb) that potently inhibited the LGR4/Wnt signaling. In drug resistant PDOs and xenograft models, treatment with LGR4-mAb significantly sensitizeddrug- 38 induced ferroptosis. Mechanistically, LGR4 dependent Wnt signaling transcriptionally up-regulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Targeting40 Wnt signaling by LGR4-mAb and by other modulators augments ferroptosis when co-administrated with chemotherapeutic agents. Finally, LGR4-mAb therapy was effective against other cancers that express high levels of LGR4. Collectively, our results demonstrate a new strategy to selectively activate ferroptosis and provide a new opportunity to fight refractoryand44 recurrent cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244082 | GEO | 2023/09/25

REPOSITORIES: GEO

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Project description:The adult stem cell marker Lgr5 and its close relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. Conditional deletion of the two genes in the gut impairs expression of Wnt target genes and results in rapid demise of intestinal crypts, thus phenocopying the effects of Wnt pathway inhibition. By mass-spectrometry, we find that Lgr4 and Lgr5 associate with the endogenous Wnt co-receptors Frizzled-5/7 and Lrp5/6 in HEK293 cells and in colorectal cancer cells. We also find that soluble Rspondin1, a Wnt pathway agonist, specifically binds to endogenous Lgr4 on HEK293 cells. In these cells, soluble Rspondin1 potently enhances canonical Wnt signals initiated by Wnt3A. Removal of Lgr4 does not affect Wnt3A-induced signals, but abrogates the Rspondin1-mediated enhancement of these signals, a phenomenon rescued by re-expression of Lgr4, -5 or -6. Rspondin1 and can be rescued by Wnt pathway activation. Lgr4/5/6 are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble Rspondin proteins. We used two different experimental setups to show that concomitant deletion of Lgr4 and Lgr5 affects the expression of Wnt pathway target genes. First, we determined the downregulated genes after Lgr4/5 deletion in AhCre_Lgr4fl/fl_Lgr5 fl/fl mice on day 1 post-deletion, before any histological changes are apparent in these mice (Lgr4/5 gene signature). Next, we acutely withheld the Wnt agonist Rspondin1 from in vitro crypt organoid cultures and performed differential gene expression before, and 1 day after withdrawal (Rspondin1 withdrawal signature). For better comparison we also deleted the Lgr4 and Lgr5 in vitro in organoids isolated from VillinCre_Lgr4fl/fl_Lgr5 fl/fl mice, and performed microarrays 1 day after deletion in vitro. Furthermore, we used published expression data from Apcfl/fl mice (Apc deletion signature). Deletion of Apc results in the immediate upregulation of Wnt pathway target genes. Comparison of the Lgr4/5 gene signature to both the Rspondin1 withdrawal signature and the Apc deletion signatures using Gene Set Enrichment Analysis (GSEA) showed that the genes deregulated after simultaneous deletion of Lgr4 and -5 are in the majority under the control of the Wnt pathway.

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Several colorectal cancer patient derived tumor organoid RNAseq data

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