1. Cancer Biology
  2. Genetics and Genomics
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Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

  1. Yiu Huen Tsang  Is a corresponding author
  2. Yumeng Wang
  3. Kathleen Kong
  4. Caitlin Grzeskowiak
  5. Oksana Zagorodna
  6. Turgut Dogruluk
  7. Hengyu Lu
  8. Nicole Villafane
  9. Venkata Hemanjani Bhavana
  10. Daniela Moreno
  11. Sarah H Elsea
  12. Han Liang
  13. Gordon B Mills
  14. Kenneth L Scott
  1. Baylor College of Medicine, United States
  2. The University of Texas MD Anderson Cancer Center, United States
  3. University of Texas MD Anderson Cancer Center, United States
Research Article
  • Cited 7
  • Views 1,312
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Cite this article as: eLife 2020;9:e48963 doi: 10.7554/eLife.48963

Abstract

The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.Source data files have been provided for Figures 1.

The following previously published data sets were used

Article and author information

Author details

  1. Yiu Huen Tsang

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    tsangsa@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0895-6854
  2. Yumeng Wang

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kathleen Kong

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Caitlin Grzeskowiak

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Oksana Zagorodna

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Turgut Dogruluk

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9212-9471
  7. Hengyu Lu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nicole Villafane

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Venkata Hemanjani Bhavana

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniela Moreno

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Sarah H Elsea

    Molecular & Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Han Liang

    Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Gordon B Mills

    Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kenneth L Scott

    Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (5R01CA211176-04)

  • Sarah H Elsea

National Institutes of Health (U24209851)

  • Gordon B Mills

Cullen Foundation

  • Turgut Dogruluk

Cancer Prevention and Research Institute of Texas (RP140102)

  • Hengyu Lu

National Institutes of Health (1F32CA221015-01)

  • Kathleen Kong

Cancer Prevention and Research Institute of Texas (RP120046)

  • Kenneth L Scott

American Association for Cancer Research (14-20-25-SCOT)

  • Kenneth L Scott

National Institutes of Health (U01CA168394)

  • Gordon B Mills

National Institutes of Health (1103109301)

  • Kenneth L Scott

Lustgarten Foundation (RFP-B-042)

  • Kenneth L Scott

National Institutes of Health (U01CA168394)

  • Kenneth L Scott

National Institutes of Health (R01CA175486)

  • Han Liang

National Institutes of Health (U24209851)

  • Han Liang

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AN-5428) of Baylor College of Medicine. The protocol was approved by the Committee on the Ethics of Animal Experiments of Baylor College of Medicine . All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Grant McArthur, Peter MacCallum Cancer Centre, Australia

Publication history

  1. Received: June 1, 2019
  2. Accepted: April 6, 2020
  3. Accepted Manuscript published: April 9, 2020 (version 1)
  4. Version of Record published: April 17, 2020 (version 2)

Copyright

© 2020, Tsang 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.

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