Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

Abstract

BackgroundOvercoming systemic dormancy and initiating secondary tumor grow under unique microenvironmental conditions is a major rate-limiting step in metastatic progression. Disseminated tumor cells encounter major changes in nutrient supplies and oxidative stresses compared to the primary tumor and must demonstrate significant metabolic plasticity to adapt to specific metastatic sites. Recent studies suggest that differential utilization of pyruvate sits as a critical node in determining the organotropism of metastatic breast cancer. Pyruvate carboxylase (PC) is key enzyme that converts pyruvate into oxaloacetate for utilization in gluconeogenesis and replenishment of the TCA cycle.MethodsPatient survival was analyzed with respect to gene copy number alterations and differential mRNA expression levels of PC. Expression of PC was analyzed in the MCF-10A, D2-HAN and the 4 T1 breast cancer progression series under in vitro and in vivo growth conditions. PC expression was depleted via shRNAs and the impact on in vitro cell growth, mammary fat pad tumor growth, and pulmonary and non-pulmonary metastasis was assessed by bioluminescent imaging. Changes in glycolytic capacity, oxygen consumption, and response to oxidative stress were quantified upon PC depletion.ResultsGenomic copy number increases in PC were observed in 16–30% of metastatic breast cancer patients. High expression of PC mRNA was associated with decreased patient survival in the MCTI and METABRIC patient datasets. Enhanced expression of PC was not recapitulated in breast cancer progression models when analyzed under glucose-rich in vitro culture conditions. In contrast, PC expression was dramatically enhanced upon glucose deprivation and in vivo in pulmonary metastases. Depletion of PC led to a dramatic decrease in 4 T1 pulmonary metastasis, but did not affect orthotopic primary tumor growth. Tail vein inoculations confirmed the role of PC in facilitating pulmonary, but not extrapulmonary tumor initiation. PC-depleted cells demonstrated a decrease in glycolytic capacity and oxygen consumption rates and an enhanced sensitivity to oxidative stress.ConclusionsOur studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1008-9) contains supplementary material, which is available to authorized users.

Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take

“…One of these adaptations has been observed during breast‐derived lung metastasis where, once early metastatic lesions are established, pyruvate further drives PC activity, which supports the TCA cycle anaplerosis needed for proliferation (Christen et al , ). Accordingly, genetic deletion of PC impaired pulmonary but not extra‐pulmonary metastasis—suggesting that PC activity could be important for organ tropism (Shinde et al , ). The metabolic changes induced by the organ microenvironment were also found to be reversible with the observation that transplanting liver metastasis‐derived cancer cells back into the primary subcutaneous site induced a parental metabolic state (Piskounova et al , ).…”

“…Another important regulator of the tumorigenic process is the tumor secretome. The secretome consists of key regulatory molecules, derived from the primary tumor or tumor‐associated cells, which influence the microenvironment of secondary organs—priming them for the cultivation of secondary tumors (Shinde et al , ). In this regard, recent metabolomics analysis of the in vivo secretome of lung cancer models revealed that increased succinate secretion into plasma by cancer cells induces macrophage‐dependent cytokine signaling in the metastatic niche (Wu et al , ).…”

PRDM16 inhibits cell proliferation and migration via epithelial to mesenchymal transition by directly targeting pyruvate carboxylase in papillary thyroid cancer

“…It is a rate-limiting enzyme that catalyzes the decarboxylation of pyruvate to form acetyl-CoA. In recent years, the role of PC in tumor cells has been gradually reported (31). Stefan Christen et al (32) found that the process of lung metastasis in breast cancer relies on the glucose metabolism pathway that PC participates in.…”

Nitroxyl as a Potential Theranostic in the Cancer Arena

“…Breast cancer is a complex, heterogeneous disease, and it is also the most cause of cancer death among women around the world (105,132,167). Glycolysis is the main energy source for most solid tumors under hypoxic environment (130,164).…”