p53 inactivation drives breast cancer brain metastasis via cell-autonomous and astrocyte-dependent increase of fatty acid metabolism
Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growth in vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53 inactivation increased fatty acid synthesis (FAS), which is known to be required for brain-metastasizing cancer cells, by upregulating SCD1, and knockout of SCD1 was sufficient to abolish the growth advantage of p53-deficient cells in the brain. Molecularly, p53 suppressed SCD1 expression by binding to its promoter, and by downregulating its novel co-activator DEPDC1. FAS was further enhanced by astrocytes in a p53-dependent manner: Expression of FAS genes, including SCD1, was elevated upon exposure of cells to astrocyte-conditioned medium, and metabolomic analyses revealed that astrocytes secreted FAS substrates that were more efficiently metabolized into MUFAs in p53-deficient BC cells. Consequently, astrocytes enhanced the survival, proliferation and migration of BC cells in a p53-dependent manner. Lastly, p53-deficient cells were more sensitive than p53-competent cells to FAS inhibitors in vitro, in vivo, and ex vivo, and patient-derived BCBM organotypic cultures were sensitive to SCD1 inhibition. In summary, our study identifies p53 inactivation as a driver of BCBM; reveals a p53-dependent effect of astrocytes on breast cancer cell behavior; and highlights FAS as an underlying, therapeutically-targetable molecular mechanism.