Unraveling the mysteries of breast cancer brain metastasis: how cancer cells hijack brain metabolism

Breast cancer is a devastating disease that, in some cases, spreads (metastasizes) to the brain, creating significant clinical challenges. The process by which breast cancer cells adapt to and thrive in the brain environment has remained largely mysterious. However, recent research has shed light on this complex process, revealing how cancer cells manipulate brain metabolism to their advantage.

The Brain’s Unique Metabolic Environment

The brain has a unique metabolic environment, where neurons (nerve cells) and astrocytes (a type of glial cell that supports neurons) work closely together. They use molecules like glutamate, glutamine, and lactate to communicate and maintain brain function. This delicate balance is crucial for the brain’s normal operations.
The Role of Extracellular Vesicles and miR-199b-5p

Researchers at the University of California San Diego have discovered that breast cancer cells with a high likelihood of spreading to the brain release tiny particles called extracellular vesicles (EVs). These EVs carry a specific microRNA, miR-199b-5p, in high amounts. MicroRNAs are small molecules that help regulate gene expression.

Interestingly, miR-199b-5p levels are significantly higher in the blood of breast cancer patients with brain metastases compared to those with metastases in other organs. This suggests a link between miR-199b-5p and the ability of breast cancer cells to colonize the brain.

EV miR-199b suppresses the expression of
EAAT2, SNAT2, and MCT2 in astrocytes and neurons

a Fluorescence (green) was detected in astrocytes (NHA) and neurons (differentiated SH-SY5Y) after an incubation with CFSE-labeled EVs for 24 h, which indicates EV uptake. A widefield image (CFSE and phase contrast), a confocal image (only showing CFSE), and orthogonal views of confocal microscopy z-stacks (CFSE and DIC) showing the 3D localization of CFSE signals are presented. b RT-qPCR-determined RNA levels of EAAT2 in astrocytes and levels of SNAT2 and MCT2 in neurons upon treatment with indicated EVs for 48 h. Data were normalized to 18S rRNA (n = 3 biological replicates). Values are shown as mean ± SD. c Western blot showing levels of indicated proteins in astrocytes and neurons upon treatment with indicated EVs for 48 h. GAPDH was used as a sample processing control. The samples derive from the same experiment but in some cases different gels for EAAT2, SNAT2, or MCT2 and another for GAPDH were processed in parallel. Unpaired two-tailed t-test was used in the top and bottom panels of b. One-way ANOVA followed by Tukey’s multiple comparison test was used in the middle panel of b. P values are indicated. 

Hijacking Brain Metabolism

So, how do these cancer cells use miR-199b-5p to their advantage? The microRNA targets specific solute carrier transporters in the brain. These transporters include:

  • SLC1A2/EAAT2: Found in astrocytes, helps manage glutamate levels.
  • SLC38A2/SNAT2 and SLC16A7/MCT2: Found in neurons, involved in transporting glutamine and lactate.

By targeting these transporters, miR-199b-5p disrupts the normal metabolic coupling between neurons and astrocytes. This disruption causes the metabolites (glutamate, glutamine, and lactate) to be retained outside the cells, creating an environment that promotes cancer cell growth.

Implications for Understanding and Treating Brain Metastasis

This study provides crucial insights into how breast cancer cells adapt to the brain environment. By hijacking the brain’s metabolic processes, these cells create a supportive niche for their growth. Understanding this mechanism opens up potential avenues for new treatments targeting these metabolic changes.

Future Directions

  1. Diagnostic Tools: Elevated levels of miR-199b-5p in the blood could serve as a biomarker for early detection of brain metastasis in breast cancer patients.
  2. Therapeutic Targets: Developing therapies that block miR-199b-5p or its effects on solute carrier transporters might help prevent or treat brain metastases.
  3. Broader Applications: Exploring whether similar mechanisms are at play in other types of cancer that metastasize to the brain.
Ruan X, Yan W, Cao M. et al. (2024) Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis. Nat Commun [Epub ahead of print]. [article]

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