Metabolic advantages and vulnerabilities in brain metastases

Abstract

Metabolic adaptations permit tumor cells to metastasize to and thrive in the brain. Brain metastases continue to present clinical challenges due to rising incidence and resistance to current treatments. Therefore, elucidating altered metabolic pathways in brain metastases may provide new therapeutic targets for the treatment of aggressive disease. Due to the high demand for glucose in the brain, increased glycolytic activity is favored for energy production. Primary tumors that undergo Warburg-like metabolic reprogramming become suited to growth in the brain microenvironment. Indeed, elevated metabolism is a predictor of metastasis in many cancer subtypes. Specifically, metabolic alterations are seen in primary tumors that are associated with the formation of brain metastases, namely breast cancer, lung cancer, and melanoma. Because of this selective pressure, inhibitors of key metabolic factors may reduce tumor cell viability, thus exploiting metabolic pathways for cancer therapeutics. This review summarizes the metabolic advantages and vulnerabilities of brain metastases.

Keywords: Brain metastases; Cancer metabolism; Metabolic adaptation.

Figure 1. EGFR amplification promotes metabolic reprogramming

A) Amplification of EGFR activates mTORC2, AKT, and c-Myc to promote metabolic reprogramming. EGFR variant III is shown as a representative mutation causing EGFR activation because it is commonly found in glioblastoma and breast cancer (77, 78). B) AKT and c-Myc (in green) activate enzymes (in blue) involved in glycolysis, the pentose phosphate pathway, and glutamine catabolism to supply energy and macromolecules to rapidly proliferating cancer cells. Reprinted by permission from Elsevier: Cell Press, copyright 2014. Masui K, Cavenee WK, Mischel PS. (2014) mTORC2 in the center of cancer metabolic reprogramming. Trends in endocrinology and metabolism: TEM. 25: 364–73. PMID: 24856037; PMCID: PMC4077930

Figure 2. Interactions between astrocytes and tumor cells support tumor growth

A) Circulating tumor cells extravasate in the brain. B) Astrocytes (in pink) release exosomes containing miRNAs that reduce PTEN expression in nearby tumor cells. C) Loss of PTEN results in release of the chemoattractant CCL2. D) CCL2 recruits IBA1+ myeloid cells (in green), which promote tumor cell proliferation and reduce apoptosis. E) The myeloid cells support tumor outgrowth in the brain. Reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 2015. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, Wang H, Ellis K, Cheerathodi M, McCarty JH, Palmieri D, Saunus J, Lakhani S, Huang S, Sahin AA, Aldape KD, Steeg PS, Yu D. (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 527: 100–4. PMID: 26479035; PMCID: PMC4819404

Figure 3. Potential role of c-Myc in metabolic dysregulation

A) Thioredoxin-interacting protein (TXNIP) typically inhibits glucose uptake and glycolytic gene expression. High TXNIP expression is associated with longer metastasis-free survival (46). B) Myc^highTXNIP^low signature is associated with metabolic reprogramming and poor prognosis in TNBC patients through reduced glucose uptake and glycolytic gene expression. C) MYC amplification is acquired during the metastatic process, which supports a general mechanism of metabolic dysregulation in BMs. This results in an aggressive, glycolytic tumor with a poor prognosis.

Figure 4. Methods of transport across the BBB and potential drug delivery routes

A–D) Common transport routes for solute molecules that are needed for normal brain metabolism. E–G) Transport routes that can be hijacked to deliver drugs to the brain. Drugs can be conjugated to insulin, transferrin, or albumin or loaded into liposomes, nanoparticles, or immune cells to utilize transcytosis pathways. Reprinted by permission from Elsevier: Advanced Drug Delivery Reviews, copyright 2011. Chen Y, Liu L. (2012) Modern methods for delivery of drugs across the blood-brain barrier. Advanced drug delivery reviews. 64: 640–65. PMID: 22154620