Mechanistic Insights into TP53 Inactivation and SCD1 Upregulation Driving Brain Metastasis in Breast Cancer

TP53 loss and SCD1 upregulation are pervasive features of breast cancer brain metastasis and are linked to aggressive disease biology; TP53 inactivation is specifically associated with this clinical phenotype. In vivo, TP53 perturbation increased the capacity of tumor cells to colonize and grow in the brain. The results therefore identify a metabolic vulnerability—upregulated fatty-acid desaturation—that may be targetable.

To test causality, the investigators used complementary in vitro systems, orthotopic and intracardiac in vivo brain-metastasis assays, and genome-scale analyses of tumor and metastasis samples. Brain colonization and metastatic growth were key functional readouts. Models with TP53 loss showed markedly higher rates of brain colonization and larger metastatic lesions than TP53-intact controls, prompting mechanistic follow-up experiments to define how TP53 perturbation drives the phenotype.

At the molecular level, p53 loss altered transcriptional control of lipid-synthesis programs: the study demonstrated p53 binding at the SCD1 promoter and reduced repression of SCD1 together with downregulation of its co-activator DEPDC1. Broader fatty-acid synthesis programs were upregulated, consistent with pathway-level metabolic rewiring. Collectively, these observations support a causal chain in which loss of p53 derepresses SCD1 transcription and shifts lipid-metabolic programs toward enhanced desaturation.

Lipidomic profiling showed increased monounsaturated fatty-acid pools, a higher MUFA-to-SFA ratio, and membrane-composition changes consistent with greater desaturation in TP53-deficient cells. Astrocyte-conditioned media further augmented these shifts by supplying substrates that were metabolized into desaturated lipids. The combined lipid and metabolic phenotype supports membrane remodeling and energetic flexibility that plausibly favor survival and proliferation in the brain microenvironment, conferring a desaturation-driven growth advantage.

Therapeutic perturbation validated SCD1 as a functional mediator: genetic SCD1 knockout abolished the p53-dependent growth advantage in multiple TP53-deficient models, and pharmacologic inhibition of fatty-acid synthesis reduced metastatic burden ex vivo and in vivo, consistent with on-target effects. TP53-deficient tumors showed the largest responses, supporting SCD1-pathway dependence and translational potential while highlighting remaining gaps for clinical translation.

Clinically, these results identify a metabolically targetable vulnerability in breast cancer brain metastasis.

Key Takeaways:

• TP53 inactivation is linked to upregulation of desaturation via SCD1 and to increased brain-colonizing capacity in preclinical models.
• Patients with TP53-deficient breast tumors appear at higher risk for brain metastasis and may represent a subgroup with actionable metabolic dependence.
• These data motivate biomarker-driven stratification and prioritization of FAS/SCD1-directed approaches in preclinical-to-clinical development.