Exosomal transfer of VPS9D1-AS1 induces M2 polarization to promote erlotinib resistance of LUAD cells via activation of the Wnt/β-catenin signaling pathway

  • Biochem Pharmacol. 2026 Jan;243(Pt 2):117537. doi: 10.1016/j.bcp.2025.117537.
Zhuoran Teng  1 ,  Jingyan Gao  2 ,  Chen Li  3 ,  Miao Wang  2 ,  Lan Li  2 ,  Yunhe Jv  2 ,  Fei Lu  2 ,  Yu Hou  4 ,  Yaoxiong Xia  5 ,  Yanping Gao  6 ,  Qiao Zhang  7
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China.
  • 2. Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China.
  • 3. Department of Scientific Research, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China.
  • 4. Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 5. Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 6. Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 7. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China. Electronic address: [email protected].
PMID: 41207568 DOI: 10.1016/j.bcp.2025.117537
Abstract

Tumor microenvironment (TME) is widely recognized as a critical effector in lung adenocarcinoma (LUAD) progression. Tumor-associated macrophages (TAMs) are the main components of TME. A substantial amount of evidence has revealed the correlation between TAMs and the survival of LUAD patients. In this study, we firstly proved that long non-coding RNA (lncRNA) VPS9 domain containing 1 antisense RNA 1 (VPS9D1-AS1) regulates erlotinib resistance in LUAD. The focus of this study is to investigate whether exosome-transmitted VPS9D1-AS1 influenced erlotinib resistance in LUAD through interacting with TAMs. Our study found that VPS9D1-AS1 could induce M2 macrophages polarization. Besides, we proved that exosomal transfer of VPS9D1-AS1 promoted M2 polarization. Moreover, exosomal transfer of VPS9D1-AS1 induce Wnt/β-catenin pathway activation by recruiting MYCN opposite strand (NCYM) to promote glycogen synthase kinase-3β (GSK-3β) ubiquitination and degradation. Meanwhile, exosomal transfer of VPS9D1-AS1 sequestered miR-532-3p to up-regulate catenin beta 1 (CTNNB1). Taken together, exosomal transfer of VPS9D1-AS1 induced M2 polarization to promote erlotinib resistance of LUAD cells through activating Wnt/β-catenin pathway.

Keywords
Erlotinib resistance; Lung adenocarcinoma; M2 polarization; VPS9D1-AS1; Wnt/β-catenin.
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