Modulation of Epithelial-Mesenchymal Transition Is a Possible Underlying Mechanism for Inducing Chemoresistance in...

Area of Science:

• Cancer Biology
• Molecular Oncology
• Drug Resistance Mechanisms

Background:

• Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis, often linked to intrinsic or acquired chemoresistance.
• Gemcitabine (GEM) and paclitaxel (PTX) are standard chemotherapeutics, but their efficacy is limited by resistance.
• The molecular underpinnings of differential resistance to GEM and PTX in pancreatic cancer remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying acquired resistance to gemcitabine (GEM) and paclitaxel (PTX) in pancreatic cancer.
• To compare the differences and similarities in resistance mechanisms between GEM and PTX in MIA PaCa-2 cells.
• To investigate the role of cellular metabolism and epithelial-mesenchymal transition (EMT) in chemoresistance.

Main Methods:

• Establishment and characterization of GEM-resistant (MIA PaCa-2-GR) and PTX-resistant (MIA PaCa-2-PR) MIA PaCa-2 cell lines.
• Analysis of 2D and 3D spheroid configurations, cellular metabolism (mitochondrial and glycolytic functions) using Seahorse bio-analyzer.
• RNA sequencing and bioinformatics analysis (Ingenuity Pathway Analysis - IPA) to identify differentially expressed genes (DEGs) and regulatory pathways.

Main Results:

• Resistant cell lines (MIA PaCa-2-GR and -PR) exhibited slower 3D spheroid formation compared to parent cells.
• Significant modulation of mitochondrial and glycolytic functions was observed in resistant cells, differing between 2D and 3D cultures.
• RNA sequencing identified EMT-related factors (e.g., STAT3, GLI1) as potential upstream regulators of drug resistance; FABP5 and GASK1B were highlighted as unique modulators of EMT.

Conclusions:

• Modulation of epithelial-mesenchymal transition (EMT) is a key molecular mechanism driving chemoresistance to GEM and PTX in pancreatic cancer cells.
• Distinct and overlapping metabolic alterations contribute to resistance against different chemotherapeutic agents.
• Identifying specific EMT modulators like FABP5 and GASK1B may offer novel therapeutic targets for overcoming chemoresistance.