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

Jie Zhang1, Jinpeng Liu1, Zhuixing Liu1

  • 1Department of Oncology, Xi'an International Medical Center Hospital, Xi'an 710100, China.

Pathology, Research and Practice
|March 16, 2025
PubMed
Abstract

Insights

Exosomes from M2-tumor-associated macrophages transfer malate dehydrogenase 1 (MDH1) to lung adenocarcinoma cells, promoting tumor growth and metastasis by activating the Hippo/YAP pathway.

Area of Science:

  • Cancer biology
  • Cellular communication
  • Molecular oncology

Background:

  • Exosomes mediate intercellular communication in cancer, originating from various cell types including tumor-associated macrophages (TAMs).
  • The role of M2-polarized TAMs (M2-TAMs)-derived exosomes (M2-exos) in transferring oncogenic proteins like malate dehydrogenase 1 (MDH1) to reprogram lung adenocarcinoma (LUAD) remains unexplored.

Purpose of the Study:

  • To investigate whether M2-TAMs-derived exosomes (M2-exos) transfer malate dehydrogenase 1 (MDH1) to lung adenocarcinoma (LUAD) cells.
  • To elucidate the mechanism by which M2-exos-derived MDH1 influences LUAD progression and the Hippo/YAP signaling pathway.

Main Methods:

  • Generation and characterization of M0-TAMs and M2-TAMs using THP-1 differentiated macrophages co-cultured with A549 cells.
  • Isolation and characterization of M0-exos and M2-exos.
  • In vivo xenograft studies to assess the impact of M2-exos-derived MDH1 on tumor growth.
  • Quantitative PCR, immunoblot, immunohistochemistry (IHC), CCK-8, EdU, colony formation, wound-healing, and transwell assays to analyze gene expression and cell phenotypes.

Main Results:

  • Bioinformatics analysis revealed MDH1 overexpression in LUAD, correlating with poor prognosis.
  • MDH1 depletion inhibited LUAD cell growth, migration, and invasiveness in vitro.
  • M2-exos were found to transfer MDH1 into LUAD cells, increasing intracellular MDH1 levels.
  • M2-exos-derived MDH1 promoted xenograft tumor growth and activated the Hippo/YAP pathway in LUAD cells.
  • Inhibition of Yes-associated protein (YAP) reversed the pro-malignant effects of M2-exos in LUAD cells.

Conclusions:

  • Exosomal MDH1 derived from M2-TAMs promotes LUAD cell growth and metastasis.
  • The mechanism involves the activation of the Hippo/YAP signaling pathway.
  • This study uncovers a novel exosomal pathway for communication between the tumor microenvironment and LUAD cells.
Keywords:
Exosomal MDH1ExosomesHippo/YAP pathwayLung adenocarcinomaM2-polarized tumor-associated macrophagesOncogenic role

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