Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Skeletal muscle loss and weakness negatively impact cancer patient prognosis and quality of life.
• Tumor-derived factors are known to induce muscle wasting (cachexia) and cell death (apoptosis).

Purpose of the Study:

• To investigate the role of extracellular vesicles (EVs) from breast cancer cells in skeletal muscle dysfunction.
• To elucidate the molecular mechanisms by which cancer EVs affect muscle mitochondria.

Main Methods:

• Analysis of mitochondrial content, function, and oxidative stress in skeletal muscle exposed to cancer EVs.
• Characterization of microRNA transfer from cancer EVs to muscle cells (myocytes).
• Investigation of TP53 (tumor suppressor) and its downstream targets in muscle cells.

Main Results:

• Breast cancer cell-secreted EVs reduce mitochondrial content, energy production, and increase oxidative stress in skeletal muscle.
• miR-122-5p within EVs transfers to myocytes, targeting TP53 and downregulating key mitochondrial genes (Tfam, Pgc-1α, Sco2, 16S rRNA).
• Restoring TP53 in muscle ameliorated mitochondrial issues and partially improved running capacity in tumor-bearing mice.

Conclusions:

• Extracellular vesicles from breast cancer cells mediate skeletal muscle mitochondrial dysfunction.
• This EV-mediated mechanism contributes to muscle weakness observed in some cancer patients.