Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer

Abstract

Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor–macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.

Metabolic guidance and stress in tumors modulate antigen-presenting cells

“…An increase of glycolysis in tumors undergoing EMT will shape the TME into a lactate-rich environment, which will further perturb proper antitumor immunity. In line with this, Zeb1 induction in breast cancer has been demonstrated to be critical for pro-tumoral macrophage polarization [ 107 ]. This intrigues the question of whether the ablation of lactate signaling in TAMs will alleviate the aggressiveness of tumor.…”

EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells

“…Among the signaling intermediates identified above, the CREB pathway is known to link PGE2 signaling with macrophage polarization [ 52 ]. In fact, a CREB-C/EBPβ cascade has been shown to induce M2 macrophage-specific gene expression [ 53 ], and was higher in M2 polarized cells [ 54 ]. M2 polarization also correlates with a predominant arginase pathway and an increased production of polyamines, which can be responsible for tumor proliferation together with an anti-inflammatory response [ 55 ].…”

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

“…In vivo and in vitro study showed that lactate induces VEGF expression and M2-like polarization of TAMs, both of which are mediated by HIF-1α [ 107 ]. Lactate targets the protein-coupled receptors on the surface of the TAMs membrane and induces M2-type polarization via the PKA/CREB pathway [ 174 ]. Additionally lactic acid produced under hypoxia is believed to be a weapon for activating pro-angiogenic TAMs and increasing PD-L1 protein expression in TAMs [ 172 , 175 , 176 ].…”