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

Oncogene volume 43, pages 434–446 (2024)Cite this article

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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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Fig. 1: LAMB3 mediates enhanced cell motility and invasiveness of MAPKi-resistant melanoma cells.
Fig. 2: The integrin α3 and α6 are required for LAMB3-mediated enhancement of invasive phenotype of MAPKi-resistant melanoma cells.
Fig. 3: SOX10 negatively regulates LAMB3.
Fig. 4: SOX10-deficiency induces LAMB3 upregulation via activating TGF-β signaling.
Fig. 5: LAMB3 regulates the expression of multiple MMPs.
Fig. 6: LAMB3 regulates MMPs through FAK.
Fig. 7: LAMB3 depletion reduces metastatic potential of MAPKi-resistant melanoma tumors in vivo.

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All data generated or analyzed during this study are included in this published article and the supplementary files.

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Acknowledgements

We thank Dr. Meenhard Herlyn (Wistar Institute, Philadelphia, PA, USA) for kindly providing the 1205Lu cells. This work was supported by the National Natural Science Foundation of China (32000541 to S. Han) and the China Postdoctoral Science Foundation (2019TQ0254, 2019M663671 to S. Han), the National Natural Science Foundation of China (82272877, 31970724 to Y. Shao), the Integrated Project of the National Science Foundation Key Program of China (92249303 to J. Liu), the Fundamental Research Funds for the Central Universities (to Y. Shao)

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Authors and 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

    Shujun Han, Mo Zhang, Xiaoyan Qu, Zihao Wu, Zongguan Huang, Jiankang Liu & Yongping Shao

  2. Department of Dermatology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710049, China

    Yiming Hu, Ying Li, Lanlan Cui & Yongping Shao

  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

    Lu Si

  4. School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China

    Jiankang Liu

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Contributions

S.H. performed most experiments with the help of M.Z., X.Q., Z.W., Z.H., Y.H., Y.L., L.C. and L.S. Y.S. and S.H. analyzed the data. S.H., Y.S. and J.L. wrote the manuscript. Y.S., J.L. and S.H. conceived and supervised the study.

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Correspondence to Jiankang Liu or Yongping Shao.

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Han, S., Zhang, M., Qu, X. et al. SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma. Oncogene 43, 434–446 (2024). https://doi.org/10.1038/s41388-023-02917-x

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