Scientists Reveal Regulatory Mechanism of Macrophages-promoted Tumor Growth

In a recent study published online in Molecular Cell, a research group led by Dr. YANG Weiwei from Shanghai Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences (CAS) and Dr. LI Guohui from Dalian Institute of Chemical Physics of CAS reported a new mechanism of macrophages-promoted tumor growth by regulating tumor cell metabolism.

 

Tumor microenvironment is a complex cellular environment in which tumor cells exist, including immune cells, fibroblasts, bone marrow-derived inflammatory cells and lymphocytes. Among the immune cells recruited to the tumor site, macrophages are particularly abundant and present at all stages of tumor progression.

 

These tumor-associated macrophages (TAMs) have been shown to promote many properties of tumor progression including tumor growth, metastasis and angiogenesis. However, molecular mechanism underlying the functions of TAMs remains poorly understood. 

 

In this study, scientists demonstrated that polarized M2 macrophages enhance 3-phosphoinositide dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin 6 (IL6). This phosphorylation facilitates PGK1-catalyzed reaction towards glycolysis by altering substrate affinity.

 

Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophages-derived IL6 abrogates macrophages-promoted glycolysis, proliferation and tumorigenesis. 

 

In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL6 expression and macrophages infiltration in human glioblastoma multiforme (GBM). It also correlates with malignance and prognosis of human GBM.

 

The results implicated the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.

 

This study was financially supported by grants from the National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences .