2. Academic Validation
  3. Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis

Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis

  • Dev Cell. 2025 Aug 7:S1534-5807(25)00471-X. doi: 10.1016/j.devcel.2025.07.014.
Jie Zheng 1,  Han She 2,  Rui Han 3,  Ju Tang 4,  Yuanyao Dou 5,  Conghua Lu 5,  Daijuan Huang 4,  Caiyu Lin 5,  Di Wu 5,  Chao He 5,  Yunxia Du 2,  Yinyu Wu 2,  Yuxi Zhang 2,  Chen Hu 5,  Mengxiao Zhu 5,  Yubo Wang 6,  Qing Huang 7,  Fan Wu 8,  Yong He 9
Affiliations

Affiliations

  • 1 Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China.
  • 2 Shock and Transfusion Department, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 3 Bishan hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing 402760, China.
  • 4 School of Medicine, Chongqing University, Chongqing 400044, China.
  • 5 Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 6 School of Medicine, Chongqing University, Chongqing 400044, China; Department of Respiratory Disease, Chongqing University Jiangjin Hospital, Chongqing 402218, China.
  • 7 Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 8 Scientific Affairs Department, Asia Pacific, Menarini Silicon Biosystem SpA, 567 Lan Gao Road, Putuo District, Shanghai 200333, China.
  • 9 Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China. Electronic address: heyong@tmmu.edu.cn.
PMID: 40812308 DOI: 10.1016/j.devcel.2025.07.014
Abstract

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is often linked to tumor metastasis, making control of metastasis crucial. Here, we identified a critical signaling hub responsible for Cancer metastasis and resistance development: mitochondrial cristae remodeling and metabolic reprogramming, using an anoikis-resistant cell model and a mouse tail vein metastasis model. EGFR-TKI-resistant cells exhibited stronger anoikis resistance (AR) and Mitochondrial Metabolism compared with sensitive cells, making them more prone to metastasis. Dysfunction of death-associated protein kinase 2 (Dapk2) altered Mic60 protein in mitochondrial cristae, increasing the abundance and compactness of the cristae and activating Mitochondrial Metabolism. Lactylation of the Mic60 protein may be the critical mechanism affecting the restructuring of mitochondrial cristae and activating Mitochondrial Metabolism. Our findings elucidate the role and underlying mechanisms of mitochondrial morphological dynamics and metabolic reprogramming in resistance and metastasis, offering potential therapeutic targets to overcome EGFR-TKI resistance and metastasis in lung Cancer.

Keywords

EGFR-TKI resistance; NSCLC; lactylation; metastasis; mitochondrial metabolism.

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