Cancer lethality is largely attributable to metastasis; however, the factors that dictate where cells metastasize are not fully elucidated. Abbott, Subudhi, Ferreira, and colleagues sought to understand how metabolic tissue microenvironments influence metastasis in triple negative breast cancer. The absolute levels of 124 metabolites were measured in the plasma and interstitial fluid of mouse tissues, including the mammary fat pad (MFP), liver, lung, kidney, and pancreas, as well as the cerebrospinal fluid. Overall, levels matched previously described metabolic characteristics of organs. Interestingly, nucleotide-related metabolites largely dictated clustering of samples, suggesting their importance in defining tissue-specific nutrient environments. To test the requirement for specific environmental nutrients to support growth, breast cancer cell auxotrophs for different nutrients were generated. Genes essential for amino acid, purine, and pyrimidine biosynthesis were each knocked out, and cells were intracardially injected into mice to examine how this impacted the sites where the cells can metastasize. Metastasis was impaired most strongly in cells auxotrophic for nucleotides, with knockout of DHODH or GART decreasing growth across all tissues in two or three out of three cell lines, respectively. In contrast, amino acid auxotrophs varied in metastatic growth between cell lines and tissues. Correlation analysis of metabolite levels with growth in different tissues indicated that single nutrients do not predict the sites where specific breast cancers can grow. To account for effects of circulation following injection, cells were directly implanted into the MFP and brain. Despite some outliers, consistent trends were observed in nutrient dependencies across injection methods. Furthermore, 13C-glucose tracing in breast cancer cells derived from mouse MFP or brain metastases supported the inability of single nutrient levels or pathway activity to predict metabolic dependencies for metastasis. The effects of broad metabolite levels on metastatic potential were measured through correlation of metabolite abundance and metastatic growth in control cells, with several metabolites demonstrating a positive correlation. These data highlight that multiple cell intrinsic and metabolic factors within the tissue microenvironment, rather than levels of a single nutrient, influence organ-specific metastasis of breast cancer cells.Abbott KL, Subudhi S, Ferreira R, Gültekin Y, Steinbuch SC, Munim MB, et al. Nutrient requirements of organ-specific metastasis in breast cancer. Nature 2026 Jan 7 Epub ahead of print.Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online athttps://aacrjournals.org/cdnews.
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