Cell, Developmental & Cancer Biology, Oregon Health & Science University , Portland, OR, USA.
Autophagy. 2020 Oct;16(10):1923-1924. doi: 10.1080/15548627.2020.1802091. Epub 2020 Aug 18.
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. Recent studies uncovered a role for in suppression of macroautophagy/autophagy implicating in tumorigenesis. The impact of cancer-associated mutations on tumor pathophysiology are less well explored. In pancreatic cancer cell models, MAGEA6 inhibits autophagy, facilitating pancreatic cancer initiation. However, autophagy places a brake on cancer progression and is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations that reinstitute autophagy. Further cancer-associated mutations of the broader genes frequently result in degradation of the corresponding protein products by proteasome-dependent machinery, potentially jeopardizing the utility of genes as immunotherapeutic targets. Altogether, our findings provide mechanistic insight into the divergent roles of during pancreatic cancer initiation and progression, and could inform cancer immunotherapeutic strategies for targeting MAGEA antigens.
黑色素瘤相关抗原家族 A（MAGEA）抗原在多种恶性肿瘤中表达，但不在成人体细胞中表达，这使它们成为癌症免疫治疗的有吸引力的靶标。最近的研究揭示了 在抑制巨自噬/自噬中的作用，暗示了 在肿瘤发生中的作用。癌症相关 的突变对肿瘤病理生理学的影响还不太清楚。在胰腺癌细胞模型中，MAGEA6 抑制自噬，促进胰腺癌的发生。然而，自噬会阻碍癌症的进展，并且在 MAGEA6 降解时被释放，MAGEA6 降解可以由营养缺乏或获得重新建立自噬的癌症相关突变引起。更广泛的 基因的进一步癌症相关突变通常导致相应的蛋白产物通过蛋白酶体依赖性机制降解，这可能危及 将 基因作为免疫治疗靶标的效用。总之，我们的研究结果为 在胰腺癌起始和进展中的不同作用提供了机制上的见解，并为针对 MAGEA 抗原的癌症免疫治疗策略提供了信息。
