Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

Yiu Huen Tsang, Yumeng Wang, Kathleen Kong, Caitlin Grzeskowiak, Oksana Zagorodna, Turgut Dogruluk, Hengyu Lu, Nicole Villafane, Venkata Hemanjani Bhavana, Daniela Moreno, Sarah H. Elsea, Han Liang, Gordon B. Mills, Kenneth L. Scott

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1 Scopus citations

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.

Original languageEnglish (US)
Article numbere48963
JournaleLife
Volume9
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Tsang, Y. H., Wang, Y., Kong, K., Grzeskowiak, C., Zagorodna, O., Dogruluk, T., Lu, H., Villafane, N., Bhavana, V. H., Moreno, D., Elsea, S. H., Liang, H., Mills, G. B., & Scott, K. L. (2020). Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression. eLife, 9, [e48963]. https://doi.org/10.7554/eLife.48963