Mitochondrial Protein Cox7b Is a Metabolic Sensor Driving Brain-Specific Metastasis of Human Breast Cancer Cells

Simple Summary What controls organotropism during cancer metastasis is still largely unknown. The "seed-and-soil hypothesis" of Stephen Paget (1889) proposes that metastatic onset strictly depends on a match between the needs of a given metastatic progenitor cell (the seed) and the resources provided by a given organ (the soil). Here, we decided to challenge this old theory in the context of cancer metabolism. Considering that metastasis can be prevented, we focused on triple-negative breast cancer brain metastasis. Comparing RNAseq data from wild-type human cancer cells and two independent brain-seeking variants, we identified cyclooxygenase 7b (Cox7b) in Complex IV of the mitochondrial electron transport chain as a driver of triple-negative breast cancer brain metastasis. Cox7b is not an easy therapeutic target and is most probably not unique in driving brain metastasis. Therefore, our general approach could be used to identify other metabolic proteins responsible for organotropism and amenable for metastasis-prevention therapy. Distant metastases are detrimental for cancer patients, but the increasingly early detection of tumors offers a chance for metastasis prevention. Importantly, cancers do not metastasize randomly: depending on the type of cancer, metastatic progenitor cells have a predilection for well-defined organs. This has been theorized by Stephen Paget, who proposed the "seed-and-soil hypothesis", according to which metastatic colonization occurs only when the needs of a given metastatic progenitor cell (the seed) match with the resources provided by a given organ (the soil). Here, we propose to explore the seed-and-soil hypothesis in the context of cancer metabolism, thus hypothesizing that metastatic progenitor cells must be capable of detecting the availability of metabolic resources in order to home in a secondary organ. If true, it would imply the existence of metabolic sensors. Using human triple-negative MDA-MB-231 breast cancer cells and two independent brain-seeking variants as models, we report that cyclooxygenase 7b (Cox7b), a structural component of Complex IV of the mitochondrial electron transport chain, belongs to a probably larger family of proteins responsible for breast cancer brain tropism in mice. For metastasis prevention therapy, this proof-of-principle study opens a quest for the identification of therapeutically targetable metabolic sensors that drive cancer organotropism.