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Theranostics 2020; 10(26):12026-12043. doi:10.7150/thno.46705 This issue Cite

Research Paper

Somatic mutational landscapes of adherens junctions and their functional consequences in cutaneous melanoma development

Praveen Kumar Korla^1#, Chih-Chieh Chen^2#, Daniel Esguerra Gracilla^1#, Ming-Tsung Lai³, Chih-Mei Chen⁴, Huan Yuan Chen⁵, Tritium Hwang¹, Shih-Yin Chen^4,6✉, Jim Jinn-Chyuan Sheu^{1,4,6,7,8,9✉}

1. Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80242, Taiwan.
2. Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
3. Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung 40343, Taiwan.
4. Genetics Center, China Medical University Hospital, Taichung 40447, Taiwan.
5. Institute of Biomedical Sciences, Academia Sinica, Taipei 11574, Taiwan.
6. School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
7. Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
8. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
9. Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80242, Taiwan.
#These authors contributed equally to this study.

✉ Corresponding authors: Dr. Shih-Yin Chen (E-mail: chenshihycmu.edu.tw) at Genetics Center, China Medical University Hospital, Taichung, 40447, TAIWAN; or Dr. Jim Jinn-Chyuan Sheu (E-mail: jimsheunsysu.edu.tw) at Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung City 80424, TAIWAN. More

Abstract

Cell-cell interaction in skin homeostasis is tightly controlled by adherens junctions (AJs). Alterations in such regulation lead to melanoma development. However, mutations in AJs and their functional consequences are still largely unknown.

Methods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts. Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software. Neo-antigen prediction was carried out using NetMHCpan tool. Cell-based fluorescence reporter assay was used to validate β-catenin activity in the presence of cadherin mutations. Clinical significance was analyzed using datasets from TCGA and other non-TCGA cohorts. Targeted gene exon sequencing and immunofluorescence staining on melanoma tissues were performed to confirm the in silico findings.

Results: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca²⁺-binding and cell-cell contacts. Mutational co-occurrence and physical dynamics analyses placed CDH6 at the center of the top-four mutated cadherins (core CDHs; all type-II), suggesting altered heterophilic interactions in melanoma development. Mutations in the intracellular domains significantly disturbed CDH6/β-catenin complex formation, resulting in β-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/β-catenin signaling. Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type. Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy.

Conclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development. Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times.

Keywords: adherens junctions (AJ), cadherin-6 (CDH6), somatic mutation, melanoma, neo-antigen

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