M2 macrophages-derived exosomal MDH1 drives lung adenocarcinoma progression via the Hippo/YAP signaling

Background: Exosomes are released by most cell types, including tumor-associated macrophages (TAMs), transfer diverse macromolecules and participate in intercellular communication in Cancer. However, whether M2-polarized TAMs (M2-TAMs)-derived exosomes (M2-exos) transmit the oncogenic protein malate dehydrogenase 1 (MDH1) to reprogram lung adenocarcinoma (LUAD) Cancer cells is unknown.

Methods: THP-1-differentiated macrophages were co-cultured with A549 cells to generate TAMs (M0-TAMs and M2-TAMs). Exosomes (M0-exos and M2-exos) were isolated from the co-culture supernatant and characterized. Xenograft studies were used to explore the effect of M2-exos-derived MDH1 on tumor growth. Expression analysis was performed by quantitative PCR, immunoblot and immunohistochemistry (IHC). Cell phenotype changes were detected by CCK-8, EdU, colony formation, wound-healing and transwell assays.

Results: Bioinformatics analyses confirmed that MDH1 was overexpressed in human LUAD and high MDH1 expression was associated with poor prognosis. MDH1 depletion resulted in the in vitro suppression of LUAD cell growth, migration and invasiveness. M2-exos contained and transferred MDH1 into LUAD cells to upregulate MDH1 level in these cells. M2-exos-derived MDH1 enhanced the growth of A549 xenograft tumors in vivo and activated the Hippo/YAP pathway in vitro. Furthermore, Yes-associated protein (YAP) depletion could abrogate M2-exos-induced enhancements in these malignant phenotypes of A549 and HCC827 LUAD cells.

Conclusion: These findings demonstrate that exosomal MDH1 derived from M2-TAMs enhance LUAD cell growth and metastasis by activating the Hippo/YAP signaling, uncovering a novel exosomal mechanism of crosstalk between tumor microenvironment and LUAD cells.

Exosomal MDH1; Exosomes; Hippo/YAP pathway; Lung adenocarcinoma; M2-polarized tumor-associated macrophages; Oncogenic role.