Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

eLife

Gordon B Mills¹  Yumeng Wang²  Han Liang³  Hengyu Lu⁴  Caitlin Grzeskowiak⁴  Oksana Zagorodna⁴  Venkata Hemanjani Bhavana⁴  Daniela Moreno⁴  Turgut Dogruluk⁴  Sarah H Elsea⁴  Kenneth L Scott⁴  Kathleen Kong⁴  Yiu Huen Tsang⁵  Nicole Villafane⁶ 

[1] Cell, Develop & Cancer Biology, Oregon Health & Science University, Portland, United States;Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, United States;Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States;Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States;Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, United States;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States;Cell, Develop & Cancer Biology, Oregon Health & Science University, Portland, United States;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States;Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, United States;

关键词: MAGEA;    autophagy;    MAGEA6;    proteasome;    pancreatic ductal adenocarcinoma;    Human;   

DOI  :  10.7554/eLife.48963

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY