Novel Pathway for Metastatic Cancer Therapy: Targeting Mitochondrial Plasticity

A study by researchers at UT Southwestern Medical Center shows that manipulation of mitochondrial shape could mitigate metastatic cancer. Their findings, published in Nature Cancer, indicate that cancer cells that have migrated are able to survive by undergoing a metabolic switch that reprograms their dependency from carbohydrates to fatty acids.  

Related Article: The Emergence of Metabolic Therapy, Unlocking a Next-Generation Cancer Treatment Strategy

Preventing Brain Metastases 

Metastatic cancer occurs when cancer cells fragment from the original tumor and migrate to other parts of the body. The team led by Srinivas Malladi, Ph.D., Assistant Professor of Pathology at UT Southwestern, focused on studying how escaped cancer cells are able to live in different parts of the body before emerging as metastatic cancer. Malladi commented, “Through mitochondrial plasticity, these cancer cells undergo metabolic reprogramming that aids their survival in the brain niche that otherwise would not be available to them. Exploiting this vulnerability could offer a way to prevent brain metastases,”. 

They used a mouse model to isolate late metastatic cells (Lat) from their brains. These cells have distinctly shaped, dot-like, mitochondria when compared to primary tumor cells, which have an elongated tubular shape. Additionally, the cells used fatty acid oxidation (FAO), suggesting that the change in shape is needed for the metabolism of fatty acids. They went on to examine whether metabolic reprogramming and FAO were possible as a result of altered mitochondrial dynamics by studying dynamin-related protein 1 (DRP1). The researchers observed a loss in cells ability to metabolize fatty acids and a return to their tubular shape after a decrease in the amount of DPR1. As well as a lower  probability of survival after the inhibition of DPR1. 

Potential for Development of New Therapies 

Understanding the traits and vulnerabilities of these cells is critical for developing strategies to prevent metastasis. The study revealed the importance of mitochondrial plasticity and its role in the survival of late metastatic cells. The researchers intend to evaluate DRP1 inhibitors to examine whether their effects could slow, prevent, or reverse metastatic cancer. The results are promising and open new avenues for the development of new therapies.

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GeneOnline Team