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.
Metrics
-
- 1,996
- views
-
- 271
- downloads
-
- 18
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Further reading
-
- Cancer Biology
In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative, and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased HIF1A transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate triple-negative breast cancer angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating HIF1A transcription. Furthermore, we discovered that STAMBPL1 regulates GRHL3 transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.
-
- Cancer Biology
- Physics of Living Systems
The tumor stroma consists mainly of extracellular matrix, fibroblasts, immune cells, and vasculature. Its structure and functions are altered during malignancy: tumor cells transform fibroblasts into cancer-associated fibroblasts, which exhibit immunosuppressive activities on which growth and metastasis depend. These include exclusion of immune cells from the tumor nest, cancer progression, and inhibition of T-cell-based immunotherapy. To understand these complex interactions, we measure the density of different cell types in the stroma using immunohistochemistry techniques on tumor samples from lung cancer patients. We incorporate these data into a minimal dynamical system, explore the variety of outcomes, and finally establish a spatio-temporal model that explains the cell distribution. We reproduce that cancer-associated fibroblasts act as a barrier to tumor expansion, but also reduce the efficiency of the immune response. Our conclusion is that the final outcome depends on the parameter values for each patient and leads to either tumor invasion, persistence, or eradication as a result of the interplay between cancer cell growth, T-cell cytotoxicity, and fibroblast activity. However, despite the existence of a wide range of scenarios, distinct trajectories, and patterns allow quantitative predictions that may help in the selection of new therapies and personalized protocols.
