Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain

Abstract

Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the non-oxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBPs) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis, and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.

ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer

“…Whereas some cancer cells do have the ability to support gluconeogenesis (Chen et al, 2015; Leithner et al, 2015), we demonstrated that the protective effect of lactate (and MP) in MDA436 cells was unaffected by siRNA-mediated knockdown of pyruvate carboxylase, the first anaplerotic enzyme in the gluconeogenic pathway (Figure 2A and S2A). This suggested that pyruvate was serving as a catabolic substrate in glucose deprived cells and that it relied on the activity of the pyruvate dehydrogenase (PDH) complex to enter the TCA cycle.…”

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…This is in contrast to the observation that the organs from which tumors that usually metastasize to the brain arise show little 13 C-acetate uptake on PET scans, indicating that this is a brain-specific adaptation. In addition to being able to use acetate as an alternate fuel, brain metastases have been observed to oxidize BCAAs and glutamine to survive and proliferate in the absence of glucose (Chen et al, 2015). Glutamine and BCAAs, like leucine, are vital to the maintenance of homeostasis in the brain.…”

“…As such, they are highly abundant in the brain, making them important fuel sources that can be readily utilized by metastatic cancer cells (Albrecht et al, 2010). In addition to their ability to utilize other substrates available in the central nervous system as described above, brain metastases also have the ability to produce their own glucose through upregulation of fructose-1,6-bisphosphatase 2 (FBP2), a key enzyme within the gluconeogenesis pathway (Chen et al, 2015). Together, these findings show that cells that metastasize to the brain, just like the cells in the brain themselves, are remarkably flexible in their ability to utilize different fuels, and suggests that this metabolic flexibility is essential for their survival in this environment.…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…Thus, as a consequence of the lactate shuttle, available glucose concentrations are variable and may be growth limiting for brain metastases. However, the brain interstitial space contains high levels of glutamine and branched chain amino acids, which can serve as alternate energy substrates to fuel the growth of metastatic breast cancer cells seeding the brain (95). Brain metastases may also adapt to limiting glucose levels by oxidizing acetate in the TCA cycle (96).…”