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A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer.

ABSTRACT: Genetic evidence suggests a role for the Wnt/β-catenin pathway in gastric cancer. However, Wnt5a, regarded as a prototypical non-canonical Wnt ligand, has also been extensively associated with this disease. Therefore, the roles of the Wnt signaling pathway in gastric cancer initiation and progression, and particularly the precise mechanisms by which the non-canonical Wnt pathway might promote the development and progression of gastric cancer, are not entirely well understood. This article analyzes publicly available gene and protein expression data and reveals the existence of a WNT5A/FZD2/FZD7/ROR2 signature, which correlates with tumor-infiltrating and mesenchymal cell marker expression. High expression of FZD7 and ROR2 correlates with a shared gene and protein expression profile, which in turn correlates with poor prognosis. In summary, the findings presented in this article provide an updated view of the relative contributions of the Wnt/β-catenin and non-canonical Wnt pathways in gastric cancer.

SUBMITTER: Astudillo P

PROVIDER: S-EPMC8047116 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer.

Astudillo Pablo P

Frontiers in cell and developmental biology 20210401

Genetic evidence suggests a role for the Wnt/β-catenin pathway in gastric cancer. However, Wnt5a, regarded as a prototypical non-canonical Wnt ligand, has also been extensively associated with this disease. Therefore, the roles of the Wnt signaling pathway in gastric cancer initiation and progression, and particularly the precise mechanisms by which the non-canonical Wnt pathway might promote the development and progression of gastric cancer, are not entirely well understood. This article analyz ...[more]

PMID: 33869179

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Project description:BACKGROUND:Despite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms. METHODS:Du145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies. RESULTS:While age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial cross-resistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression level altered the sensitivity of prostate cancer cells to both drugs identifying a possible new target for taxane resistance. CONCLUSION:Our study represents the first demonstration that while Wnt pathway seems to play an important role in taxanes resistance, Wnt effectors responsible for taxane specificity remain un-identified prompting the need for more studies.

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A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer.

Publications

A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer.

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