Mapping the single-cell landscape of acral melanoma and analysis of the molecular regulatory network of the tumor microenvironments

  1. Zan He
  2. Zijuan Xin
  3. Qiong Yang
  4. Chen Wang
  5. Meng Li
  6. Wei Rao
  7. Zhimin Du
  8. Jia Bai
  9. Zixuan Guo
  10. Xiuyan Ruan
  11. Zhaojun Zhang
  12. Xiangdong Fang  Is a corresponding author
  13. Hua Zhao  Is a corresponding author
  1. General Hospital of People's Liberation Army, China
  2. Chinese Academy of Sciences, China

Abstract

Acral melanoma (AM) exhibits a high incidence in Asian patients with melanoma, and it is not well treated with immunotherapy. However, little attention has been paid to the characteristics of the immune microenvironment in AM. Therefore, in this study, we collected clinical samples from Chinese patients with AM and conducted single-cell RNA sequencing to analyze the heterogeneity of its tumour microenvironments (TMEs) and the molecular regulatory network . Our analysis revealed that genes, such as TWIST1, EREG, TNFRSF9, and CTGF could drive the deregulation of various TME components. The molecular interaction relationships between TME cells, such as MIF-CD44 and TNFSF9-TNFRSF9, might be an attractive target for developing novel immunotherapeutic agents.

Data availability

Sequencing data have been deposited in GSA under accession codes HRA001804.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zan He

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zijuan Xin

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Qiong Yang

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chen Wang

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Meng Li

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Wei Rao

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhimin Du

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jia Bai

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Zixuan Guo

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiuyan Ruan

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Zhaojun Zhang

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Xiangdong Fang

    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
    For correspondence
    fangxd@big.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Hua Zhao

    Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China
    For correspondence
    hualuck301@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7139-1844

Funding

National Natural Science Foundation of China (81672698)

  • Hua Zhao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All samples were obtained from the General Hospital of the People's Liberation Army, Beijing, China. All volunteers signed informed consent prior to sample acquisition. Four primary AM tissues, three paracancerous tissues, and a metastatic lymph gland sample were included in this cohort. This study was approved by the Ethics Committee of Chinese PLA General Hospital and complied with all relevant ethical regulations(Approval No. S2021-626).

Copyright

© 2022, He et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,001
    views
  • 443
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Zan He
  2. Zijuan Xin
  3. Qiong Yang
  4. Chen Wang
  5. Meng Li
  6. Wei Rao
  7. Zhimin Du
  8. Jia Bai
  9. Zixuan Guo
  10. Xiuyan Ruan
  11. Zhaojun Zhang
  12. Xiangdong Fang
  13. Hua Zhao
(2022)
Mapping the single-cell landscape of acral melanoma and analysis of the molecular regulatory network of the tumor microenvironments
eLife 11:e78616.
https://doi.org/10.7554/eLife.78616

Share this article

https://doi.org/10.7554/eLife.78616

Further reading

    1. Cancer Biology
    2. Genetics and Genomics
    Joakim W Karlsson, Vasu R Sah ... Jonas A Nilsson
    Research Article

    Uveal melanoma (UM) is a rare melanoma originating in the eye’s uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients with uveal melanoma metastases succumb to disease within 2 years. This study aimed to provide a path toward enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA-seq of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR-seq, and the TCRs were matched to those found in single-cell sequencing data from biopsies, expanded TILs, and in livers or spleens of PDX models injected with TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.

    1. Cancer Biology
    Samarjit Jana, Mainak Mondal ... Kumaravel Somasundaram
    Research Article

    In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.