Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression
- Baylor College of Medicine, United States
- The University of Texas MD Anderson Cancer Center, United States
- University of Texas MD Anderson Cancer Center, United States
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.
Article and author information
Author details
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.
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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Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression
eLife 9:e48963.
https://doi.org/10.7554/eLife.48963
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