Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Epithelial-to-mesenchymal transition (EMT) is a process that enhances tumor progression and drug resistance.
• Few vulnerabilities of EMT-induced cancer cells have been identified.
• Understanding these vulnerabilities is crucial for developing targeted therapies.

Purpose of the Study:

• To identify novel vulnerabilities of cancer cells that have undergone EMT.
• To investigate the role of endoplasmic reticulum (ER) stress response in EMT-associated malignancy.
• To explore the therapeutic potential of targeting ER stress in EMT.

Main Methods:

• Utilized small molecules as probes to induce and study EMT.
• Assessed cellular sensitivity to agents perturbing ER function.
• Analyzed ER morphology, unfolded protein response (UPR) activation, and gene expression in EMT cells.
• Correlated EMT gene expression with ECM and PERK-eIF2α pathway genes in human tumor tissues.

Main Results:

• Induction of EMT sensitizes cancer cells to ER stress-inducing agents.
• EMT cells exhibit increased synthesis and secretion of extracellular matrix (ECM) proteins, leading to ER stress.
• EMT cells display a branched ER morphology and constitutively activate the PERK-eIF2α axis of the UPR.
• PERK-eIF2α pathway activation is essential for EMT cell invasion and metastasis.
• In human tumors, EMT gene expression correlates with ECM and PERK-eIF2α genes.

Conclusions:

• EMT confers a vulnerability to ER stress in cancer cells.
• The PERK-eIF2α pathway is critical for maintaining ER homeostasis and is indispensable for EMT cell invasion and metastasis.
• Targeting the PERK-eIF2α pathway represents a potential therapeutic strategy against EMT-driven cancers.