PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer

Abstract

Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…PDK1, which inhibits PDH (pyruvate dehydrogenase) to prevent the conversion of pyruvate to acetyl-coA, is specifically required to efficiently promote the formation of liver metastases, and is highly expressed in liver metastases from human breast cancer patients. Finally, in contrast to the primary tumor, silencing PDK1 in liver-metastatic breast cancer cells induces a dramatic reduction in liver metastatic burden (45). These results raise the idea that particular metabolic programs may better equip metastatic breast cancer cells to survive and colonize distinct metastatic microenvironments (Fig.…”

“…Recent work has demonstrated that tumor cell metabolic profiles can differ depending on their metastatic potential. By analyzing the metabolic profiles of various breast cancer cell lines that possess different metastatic abilities, we and others have shown that both glycolysis and OXPHOS are increasingly engaged as metastatic ability is acquired (45,46).…”

“…Using organ-selective breast cancer variants obtained by in vivo selection, we have demonstrated that metastatic breast tumor cells differentially engage distinct metabolic strategies depending on their metastatic site. Breast cancer cells isolated from bone or lung metastases preferentially engage OXPHOS, compared with liver-metastatic breast cancer cells that prioritize glycolysis (45). The unique metabolic profile of livermetastatic breast cancer cells was associated with engagement of HIF-1a-and pyruvate dehydrogenase kinase1 (PDK1)-dependent pathways.…”

Distinctive properties of metastasis-initiating cells

“…cancer cells to efficiently colonize the liver (Dupuy et al 2015). Another recent study has demonstrated the necessity of scavenging energy from the extracellular environment to overcome liver metabolic stress .…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Pri mary can cer cells of ten dis play ex ten sive meta bolic het ero gene ity and en gage dis tinct meta bolic pat terns de pend ing on their site of metas ta sis: in breast can cer, aer o bic gly col y sis was the dom i nant meta bolic phe no type specif i cally iden ti fied in liver metas ta sis, com pared to bone and lung metas tases that were more de pen dent on OX PHOS [199]. In an in de pen dent study [187], metasta tic breast can cer cells with a se lec tive tro pism for the brain dis played in creased gly col y sis cou pled to TCA cy cle and in creased mi to chon dr ial res pi ra tion, PPP flux and fatty acid β ox i da tion com pared to parental cir cu lat ing can cer cells.…”