Targeting Stem Cells and Dysplastic Features with Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1005652 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25648025_1.fastq.gz | Fastqsanger.gz | |||
| SRR25648025_2.fastq.gz | Fastqsanger.gz | |||
| SRR25648026_1.fastq.gz | Fastqsanger.gz | |||
| SRR25648026_2.fastq.gz | Fastqsanger.gz |
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Project description:Pre-cancerous metaplasia progression to dysplasiasignificantlyincreases the risk of gastriccancer, and effective targeting strategies forpre-cancerouslesions are currently lacking.Weaimed to identify key signaling pathways critical for stem cell survival and function in dysplasia.Usingmouse and humanmetaplastic and dysplastic organoids, we evaluated responsestoPyrvinium, a putative anti-cancer drug.WhilePyrvinium induced growth arrest in metaplasticorganoids, itinducedcell death in dysplastic organoidsthrough a dual blockade of MEK/ERKand STAT3 signaling pathways. Pyrvinium specifically targeted stem cells andproliferating cellsin dysplastic organoids.Pyrviniumarrestedmetaplasia progression andpromoted repopulationof themousestomach mucosawith normal lineages.Furthermore, Pyrvinium exhibitedsuppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blockingthe MEK/ERK and STAT3 signaling pathways.Therefore, ourfindings suggest that Pyrvinium is a promising therapeutic agent for reprogramming the pre-cancerous milieu to prevent of gastric cancer development.
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Project description:Backgrounds & aimsPrecancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia.MethodsTo assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo.ResultsAlthough pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways.ConclusionsThrough its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.
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Project description:Carcinogenesis is a multistep process in which cells accumulate multiple genetic alterations, as they progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through preneoplastic lesion/benign tumor to cancer. Histologically, progression to invasive oral squamous cell carcinoma (OSCC) follows multistep ordered series beginning with mucosal epithelial cell hyperplasia, followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore speculated that genetic alterations-mediated multistep carcinogenesis would be involved in OSCC development, but their detailed molecular mechanisms are unknown. Herein, we clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data obtained from an OSCC pathological specimen, which consists of non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion. Numerous numbers of gene expression and signal activation were altered in the OSCC development. Of them, the expression of p63 was increased and MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion as well as in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ lesions and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were merged at high frequency in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and EGFR-MEK/ERK-MAPK cooperatively induce ARL4C expression in OSCC cells. These results suggest that the stepwise activation of p63 and EGFR-MEK/ERK-MAPK contributes to OSCC tumor cell growth though regulation of ARL4C expression.
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