MicroRNAs Regulate Metabolic Phenotypes During Multicellular Tumor Spheroids Progression.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer cells alter metabolism to meet energy demands during tumor progression.
• MicroRNAs (miRNAs) are key regulators of gene expression, impacting mRNA translation and stability.
• Dysregulated metabolism is a hallmark of cancer, making it a target for therapeutic strategies.

Purpose of the Study:

• To investigate the relationship between miRNAs and metabolic target mRNAs in breast cancer.
• To understand how this regulation changes across different tumor stages (proliferative vs. quiescent).
• To identify specific miRNA-mRNA interactions influencing metabolic pathways in a 3D breast cancer model.

Main Methods:

• Paired analysis of RNA-sequencing (RNA-seq) and small RNA-sequencing (small RNA-seq) in MCF7 breast cancer cells.
• Culture of cells in monoculture and multicellular tumor spheroid (MCTS) models.
• Comparison of miRNA and mRNA expression profiles at proliferative and quiescent MCTS stages.

Main Results:

• Identification of novel direct regulatory interactions between miRNAs and metabolic mRNAs in proliferative and quiescent breast cancer stages.
• Suggested role for miR-3143 in regulating carbon metabolism by targeting hexokinase-2.
• Found that specific miRNAs can inversely regulate mRNAs involved in glycerophospholipid and N-Glycan metabolism, with stage-specific expression patterns.

Conclusions:

• MiRNAs play a significant role in modulating the metabolic landscape of breast cancer within a 3D microenvironment.
• Stage-specific miRNA-mRNA interactions contribute to metabolic reprogramming during tumor progression.
• Understanding these regulatory networks can inform the development of novel cancer therapeutics targeting metabolic vulnerabilities.