Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Abstract

A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism

“…In tumors, glycolytic intermediates are diverted to generate precursors for the biosynthesis of anabolic molecules, and molecules controlling the cellular redox state. For example, serine synthesis from glucose through phosphoglycerate dehydrogenase (PHGDH) sustains protein, heme, and nucleotide biosynthesis even when serine availability is low [27][28][29] . Additionally, PHGDH activity results in the conversion of glutamate to α-ketoglutarate in order to replenish the tricarboxylic acid (TCA) cycle, thus allowing pyruvate-derived acetyl-coA to be used for fatty acid synthesis 30,31 .…”

“…Similar observations have been made when it comes to brain metastasis. Indeed, brain metastases have been found to mainly use acetate instead of glucose and glutamine for fueling OXPHOS 130,131 , whereas they are also characterized by high levels of de novo serine biosynthesis through PHGDH for coping with a scarcity of serine and glycine in the brain 29 (Figure 4). In accordance, several studies have highlighted the role of metabolic reprogramming required for colorectal cancer (CR) to metastasize to the liver.…”

Local production of lactate, ribose phosphate, and amino acids by human triple-negative breast cancer

“…Previous studies have highlighted the penchant for TNBC cells with high PHGDH expression to synthesize serine from glucose when cultured or implanted as xenografts into mice. 56,57 The observation of strongly elevated serine and glycine synthesis in select intact human tumors argues for further efforts to pharmacologically target these pathways, perhaps using PHGDH expression and/or isotope tracing as a patient selection criterion. 56,58,59 ll We also observed TNBC synthesis of amino acids branching from the TCA cycle: aspartate; glutamate; glutamine; and proline (but not asparagine).…”