E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer.
• Germline mutations in CDH1 predispose individuals to Hereditary Diffuse Gastric Cancer syndrome.
• A synthetic lethal approach is being used to find druggable vulnerabilities in CDH1-mutant cancers.

Purpose of the Study:

• To identify protein classes affected by CDH1 mutation using genome-wide RNAi screens.
• To characterize the synthetic lethal relationship between E-cadherin and selected protein classes.
• To find potential therapeutic targets in CDH1-mutant cancers.

Main Methods:

• Genome-wide RNAi screen in isogenic MCF10A and MCF10A-CDH1-/- cells.
• Drug sensitivity assays in E-cadherin-mutant and wild-type breast and gastric cancer cell lines.
• Quantification of endocytosis efficiency and pathway metagene expression analysis.

Main Results:

• CDH1 mutation altered sensitivity to inhibitors of the PI3K/AKT pathway, GPCRs, ion channels, and ubiquitinylation enzymes.
• CDH1-mutant cells showed increased sensitivity to compounds disrupting plasma membrane trafficking.
• Reduced endocytosis capacity and identification of 20 potential synthetic lethal pathways in tumors were observed.

Conclusions:

• E-cadherin loss disrupts receptor signaling and plasma membrane organization.
• These disruptions create vulnerabilities that can be targeted therapeutically.
• The study identified potential synthetic lethal targets for CDH1-mutant cancers.