LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression

Xinxin Gan; Jiatao Hu; Qingyang Pang; Rui Yan; Yi Bao; Ying Liu; Jiaao Song; Zheng Wang; Weihao Sun; Fuzhao Huang; Chen Cai; Linhui Wang

doi:10.1002/mc.23737

LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression

Mol Carcinog. 2024 May 23. doi: 10.1002/mc.23737. Online ahead of print.

Authors

Xinxin Gan^{1

2}, Jiatao Hu¹, Qingyang Pang¹, Rui Yan¹, Yi Bao³, Ying Liu¹, Jiaao Song¹, Zheng Wang¹, Weihao Sun¹, Fuzhao Huang¹, Chen Cai⁴, Linhui Wang^{1

2}

Affiliations

¹ Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China.
² School of Materials Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China.
³ Department of Urology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ Department of Special Clinic, Changhai Hospital, Naval Medical University, Shanghai, China.

PMID: 38780182
DOI: 10.1002/mc.23737

Abstract

Lactate dehydrogenase A (LDHA) is known to promote the growth and invasion of various types of tumors, affects tumor resistance, and is associated with tumor immune escape. But how LDHA reshapes the tumor microenvironment and promotes the progression of renal cell carcinoma (RCC) remains unclear. In this study, we found that LDHA was highly expressed in clear cell RCC (ccRCC), and this high expression was associated with macrophage infiltration, while macrophages were highly infiltrated in ccRCC, affecting patient prognosis via M2-type polarization. Our in vivo and in vitro experiments demonstrated that LDHA and M2-type macrophages could enhance the proliferation, invasion, and migration abilities of ccRCC cells. Mechanistically, high expression of LDHA in ccRCC cells upregulated the expression of EPHA2 in exosomes derived from renal cancer. Exosomal EPHA2 promoted M2-type polarization of macrophages by promoting activation of the PI3K/AKT/mTOR pathway in macrophages, thereby promoting the progression of ccRCC. All these findings suggest that EPHA2 may prove to be a potential therapeutic target for advanced RCC.

Keywords: EPHA2; exosomes; lactate dehydrogenase A; macrophage; renal cell carcinoma.

Abstract

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