Details

Autor(en) / Beteiligte

• Long, Jaclyn S
• Kania, Elżbieta
• McEwan, David G
• Barthet, Valentin J A
• Brucoli, Martina
• Ladds, Marcus J G W
• Nössing, Christoph
• Ryan, Kevin M

Titel

ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2022-07, Vol.119 (28), p.e2113465119

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The role of autophagy in cancer is complex. Both tumor-promoting and tumor-suppressive effects are reported, with tumor type, stage and specific genetic lesions dictating the role. This calls for analysis in models that best recapitulate each tumor type, from initiation to metastatic disease, to specifically understand the contribution of autophagy in each context. Here, we report the effects of deleting the essential autophagy gene in a model of pancreatic ductal adenocarcinoma (PDAC), in which mutant and mutant are induced in adult tissue leading to metastatic PDAC. This revealed that loss in the presence of and was tumor promoting, similar to previous observations in tumors driven by embryonic and deletion of . However, hemizygosity also enhanced tumor initiation and progression, even though this did not ablate autophagy. Moreover, despite this enhanced progression, fewer hemizygous mice had metastases compared with animals wild type for this allele, indicating that ATG7 is a promoter of metastasis. We show, in addition, that tumors have comparatively lower levels of succinate, and that cells derived from tumors are also less invasive than those from tumors. This effect on invasion can be rescued by ectopic expression of in cells, without affecting the autophagic capacity of the cells, or by treatment with a cell-permeable analog of succinate. These findings therefore show that ATG7 has roles in invasion and metastasis that are not related to the role of the protein in the regulation of autophagy.