2. Academic Validation
  3. The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer

  • Bone Res. 2024 Aug 27;12(1):47. doi: 10.1038/s41413-024-00350-8.
Kun Li # 1 2 3,  Bo Yang # 4,  Yingying Du # 4,  Yi Ding 4,  Shihui Shen 4 5,  Zhengwang Sun 1,  Yun Liu 4,  Yuhan Wang 4,  Siyuan Cao 4,  Wenjie Ren 4,  Xiangyu Wang 4,  Mengjuan Li 4,  Yunpeng Zhang 4,  Juan Wu 6,  Wei Zheng 7 8 9,  Wangjun Yan 10,  Lei Li 11 12 13
Affiliations

Affiliations

  • 1 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2 Health Science Center, East China Normal University, Shanghai, 200241, China.
  • 3 Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China.
  • 4 School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 5 Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China.
  • 6 Department of Pharmacy The General Hospital of Western Theater Command, Chengdu, 610083, China.
  • 7 Orthopaedic Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. wei_zheng6868@163.com.
  • 8 Department of Orthopedics, General Hospital of Western Theater Command, Chengdu, 610000, China. wei_zheng6868@163.com.
  • 9 College of Medicine, Southwest Jiaotong University, Chengdu, 610031, P. R. China. wei_zheng6868@163.com.
  • 10 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. wangjun_yan1234@163.com.
  • 11 Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China. lli@bio.ecnu.edu.cn.
  • 12 School of Life Sciences, East China Normal University, Shanghai, 200241, China. lli@bio.ecnu.edu.cn.
  • 13 Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China. lli@bio.ecnu.edu.cn.
  • # Contributed equally.
PMID: 39191757 DOI: 10.1038/s41413-024-00350-8
Abstract

While KRAS mutation is the leading cause of low survival rates in lung Cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung Cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung Cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 Inhibitor was effective against KRAS-mutant lung Cancer bone metastasis by triggering Ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung Cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

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