Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis

Abstract

Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to α-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo C tracer analysis. We discovered that lung metastases have higher PC-dependent anaplerosis compared to primary breast cancers. Based on in vitro analysis and a mathematical model for the determination of compartment-specific metabolite concentrations, we found that mitochondrial pyruvate concentrations can promote PC-dependent anaplerosis via enzyme kinetics. In conclusion, we show that breast cancer cells proliferating as lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment.

Metabolic Interactions in the Tumor Microenvironment

“…Indeed, even simple approaches utilizing these principles have led to important insights [58, 59, 76]. More elegant models, albeit limited in experimental flexibility, have been important in pushing the boundaries of our understanding of tumor metabolism in vivo, illustrating the importance of context [4, 5, 8–10]. Future studies integrating these concepts and techniques will be critical to more clearly elucidate the metabolic role of the TME and associated therapeutic vulnerabilities.…”

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…In non-small cell lung cancer (NSCLC), pyruvate carboxylase (PC) expression is upregulated in the primary tumors compared to normal tissues (Sellers et al, 2015). Increased PC-dependent anaplerosis has also been observed in growing lung metastases in vivo (Christen et al, 2016). In this study, it was shown that lung metastases upregulate PC expression and prefer utilizing pyruvate over glutamine to fuel the TCA, similar to what is observed in certain NSCLCs (Sellers et al, 2015).…”

The contributions of cancer cell metabolism to metastasis

“…Although tumour cells can hijack nutrients from the cells they encounter as they arrive in an organ, nutrient availability might vary substantially between different organs. For instance, the availability of pyruvate in lungs activates pyruvate carboxylase (PC) in metastatic breast cancer cells, which in turn converts pyruvate to oxaloacetate, thereby enhancing anaplerosis (Box 1) (Christen et al, 2016). Additional studies carried out on in vitro three-dimensional (3D) models have revealed that breast cancer cells rely on the non-essential amino acid proline, through proline dehydrogenase enzyme (PRODH) activity, to form spheroids in vitro and lung metastases in vivo (Elia et al, 2017).…”