How important are nutrients to cancer cell metastasis?

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Nancy Paz

Can scientists predict which nutrients facilitate the metastatic potential of cancer? Just like humans, cancer cells will get off the sofa for their favorite snacks. But if the snack is not enticing enough, just like cancer cells, we tend to stay put in place. Metastatic potential is the likelihood that cancer will spread from the primary organ where it started and proceed to colonize a more distant site or organ in the body. Metastatic cancer can spread to almost any part of the body and different types of cancer are more likely to spread to certain areas over others.¹

The ability to predict metastatic potential is an incredibly important research question as we now know that the spread of cancer cells from primary tumor sites to distant organs has a significant impact on cancer survival rates and treatment strategies.² A recent publication in Nature from the laboratories of Rakesh Jain and George Church³ tested the hypothesis that restricting certain nutrients to cancer cells such as amino acids (the building blocks of proteins) or nucleotides (the building blocks of DNA) may actually coerce cancer cells to reduce their metastatic potential.

The type of cancer that was selected for this study was a type of breast cancer known as triple negative breast cancer (TNBC). TNBC is an aggressive type of breast cancer that lacks estrogen receptors, progesterone receptors, and excess HER2 protein. This means that TNBC does not respond to hormonal therapies or therapies that target HER2, making treatment options more limited compared to other breast cancer types. TNBC tends to grow and spread faster, has a higher rate of recurrence, and generally has a worse prognosis.⁴

A total of 124 different nutrients were selected for this assessment. They were grouped by biochemical pathway. Fluids from 6 different tissues were collected from experimental mice to measure intrinsic nutrient levels. The tissue fluids collected were plasma (liquid part of blood), cerebrospinal fluid (taken as a surrogate for brain extracellular fluid), and the interstitial fluid (clear watery fluid that fills the spaces between cells) of the mammary fat pad, liver, lung, kidneys, and pancreas. In these models, the mammary fat pad was selected as the site of the TNBC.

Following fluid isolation from the tissues, the absolute levels of the nutrients were determined.

Nutrient levels varied widely across tissues 

Nutrient availability varied widely across the different tissue fluids measured. For example, tissues associated with higher glucose metabolism, such as the liver, had higher glucose levels than plasma. The nutrients in the various tissues were at expected levels. This information provided context as to the metabolic environments that TNBC cells would find themselves in.

Single nutrients do not predict metastasis

However, taking a bigger view of the distribution of these nutrients, one can ask if it is possible to restrict cancer spread by limiting just a single nutrient? Asking this question involves thinking about limiting nutrients inside the cancer cells as opposed to their outside environment.

To answer this, the TNBC metastatic cell lines were genetically engineered to be auxotrophs. Auxotrophs are organisms that cannot synthesize specific organic compounds required for their growth. The metastatic TNBC cells were engineered to be single genetic deletions to certain enzymes that produce nucleotides and amino acids. Then, those TNBC cells were tested for their metastatic potential to different organs.

The strongest single nutrient defect that most impaired metastasis was the class of auxotroph that had deficient nucleotide levels. Nucleotides are the basic building blocks of nucleic acids, such as DNA and RNA which store and transmit genetic information. As a result, nucleotides are nutrients or metabolites that are generated from the inside of cells.

In one case, it was observed that glycinamide ribonucleotide transformylase (GART), the enzyme responsible for the synthesis of the purine class of nucleotides, needed to be expressed and present in the cell despite being surrounded by abundant levels of one type of purine, hypoxanthine. In this case, even though the cells were bathed in abundant levels of purine, the cell still needed a functional purine building machinery inside the cell to metastasize. In essence, to predict which tissues cancer cells can metastasize to one must consider information from multiple intrinsic and extrinsic metabolites. 

Multiple metabolites influence metastasis

As single nutrient profiles do not reliably predict metastasis, the scientific teams then asked if looking at a broader panel of metabolites could predict metastasis. That certainly appeared to be the case, as assessing a larger panel of metabolites showed that metastatic potential increased significantly with increasing levels of specific metabolites. Effectively, the higher the level of certain metabolites the greater the tendency of cancer cells to spread to other organs. The classes of metabolites that were positively correlated with higher metastatic potential were several nonessential amino acids (serine, glycine, tyrosine, and glutamate), several nucleotides (inosine and thymidine), and other lipid and carbohydrate-related metabolites. These studies suggest that metastatic preference (getting off the proverbial snack-laden sofa) is driven by a combination of multiple nutrient levels and intrinsic cell factors.

Take home message:

Limiting nutrient availability of single metabolites in TNBC cells may have an impact on metastasis but not reliably across all organs tested. There is a complex interplay between nutrients in the tumor microenvironment and cell-intrinsic wiring that shapes metastasis growth and expansion. Overall, the elegance of these experiments is hard to capture in a few words. However, these studies identified a strong dependency in TNBC cells on the enzyme GART to form tumors in multiple tissues. There is still more research to be carried out in this area but there is great hope for this approach.

Study limitations:

This study was performed in laboratory models that provided insight only into TNBC metabolic dependencies and that relationship to its metabolic environments. No single metastasis laboratory model will recapitulate metastasis as observed in a clinical setting.

Header Image Source: retrieved by author from Microsoft Copilot

Edited by Colin Ong

References

1. National Cancer Institute. Metastatic cancer. Updated 2024. Accessed January 29, 2026. https://www.cancer.gov/types/metastatic-cancer
2. Abbas GH, Khouri ER, Thaher O, et al. Predictive modeling for metastasis in oncology: current methods and future directions. Ann Med Surg. 2025;87:3489‑3508. doi:10.1097/MS9.0000000000003279
3. Abbott KL, Subudhi S, Ferreira R, et al. Nutrient requirements of organ‑specific metastasis in breast cancer. Nature. 2026;published online January 7, 2026. doi:10.1038/s41586‑025‑09898‑9
4. American Cancer Society. Triple‑negative breast cancer. Updated June 25, 2025. Accessed January 29, 2026. https://www.cancer.org/cancer/types/breast-cancer/about/types-of-breast-cancer/triple-negative.html.