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

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

Proceedings of the National Academy of Sciences of the United States of America 2022 Jul 12

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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 Atg7 in a model of pancreatic ductal adenocarcinoma (PDAC), in which mutant KrasG12D and mutant Trp53172H are induced in adult tissue leading to metastatic PDAC. This revealed that Atg7 loss in the presence of KrasG12D/+ and Trp53172H/+ was tumor promoting, similar to previous observations in tumors driven by embryonic KrasG12D/+ and deletion of Trp53. However, Atg7 hemizygosity also enhanced tumor initiation and progression, even though this did not ablate autophagy. Moreover, despite this enhanced progression, fewer Atg7 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 Atg7+/- tumors have comparatively lower levels of succinate, and that cells derived from Atg7+/- tumors are also less invasive than those from Atg7+/+ tumors. This effect on invasion can be rescued by ectopic expression of Atg7 in Atg7+/- 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.

Citation

Jaclyn S Long, Elżbieta Kania, David G McEwan, Valentin J A Barthet, Martina Brucoli, Marcus J G W Ladds, Christoph Nössing, Kevin M Ryan. ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2022 Jul 12;119(28):e2113465119