SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma

  • Oncogene. 2023 Dec 15. doi: 10.1038/s41388-023-02917-x.
Shujun Han  1 ,  Mo Zhang  1 ,  Xiaoyan Qu  1 ,  Zihao Wu  1 ,  Zongguan Huang  1 ,  Yiming Hu  2 ,  Ying Li  2 ,  Lanlan Cui  2 ,  Lu Si  3 ,  Jiankang Liu  4  5 ,  Yongping Shao  6  7
Affiliations
  • 1. Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
  • 2. Department of Dermatology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710049, China.
  • 3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Research Institute, Beijing, 100142, China.
  • 4. Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. [email protected].
  • 5. School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China. [email protected].
  • 6. Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. [email protected].
  • 7. Department of Dermatology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710049, China. [email protected].
PMID: 38102338 DOI: 10.1038/s41388-023-02917-x
Abstract

Melanoma that develops adaptive resistance to MAPK inhibitors (MAPKi) through transcriptional reprograming-mediated phenotype switching is associated with enhanced metastatic potential, yet the underlying mechanism of this improved invasiveness has not been fully elucidated. In this study, we show that MAPKi-resistant melanoma cells are more motile and invasive than the parental cells. We further show that LAMB3, a β subunit of the extracellular matrix protein laminin-332 is upregulated in MAPKi-resistant melanoma cells and that the LAMB3-Integrin α3/α6 signaling mediates the motile and invasive phenotype of resistant cells. In addition, we demonstrate that SOX10 deficiency in MAPKi-resistant melanoma cells drives LAMB3 upregulation through TGF-β signaling. Transcriptome profiling and functional studies further reveal a FAK/MMPs axis mediates the pro-invasiveness effect of LAMB3. Using a mouse lung metastasis model, we demonstrate LAMB3 depletion inhibits the metastatic potential of MAPKi-resistant cells in vivo. In summary, this study identifies a SOX10low/TGF-β/LAMB3/FAK/MMPs signaling pathway that determines the migration and invasion properties of MAPKi-resistant melanoma cells and provide rationales for co-targeting LAMB3 to curb the metastasis of melanoma cells in targeted therapy.

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