Doctoral Defense in Biomedical and Medical Sciences - Clémence Larat

On Monday, June 2, 2025, Clémence Larat will defend her doctoral dissertation in Biomedical and Medical Sciences at the Faculty of Medicine, University of Iceland. The dissertation is titled: An isoform specific role of the autophagy protein ATG7 in cancer.

Opponents are Dr. Thomas McWilliams, Associate Professor at the University of Helsinki, and Dr. Sigurdís Haraldsdóttir, Associate Professor at the Faculty of Medicine.

The academic advisor and supervisor was Professor Margrét Helga Ögmundsdóttir. Other members of the doctoral committee were Assistant Professor Bylgja Hilmarsdóttir, Associate Professor Siggeir Fannar Brynjólfsson, and Professor Vignir Helgason.

Professor Sædís Sævarsdóttir, Vice-Dean of the Faculty of Medicine, will chair the ceremony, which will take place in the Ceremonial Hall of the University of Iceland (Hátíðasalur) and begins at 1:00 PM.

Abstract

Autophagy is a cellular degradation process, important for maintaining cellular homeostasis. It has been shown to be involved in cancer initiation and development, either in a tumour-suppressive or promotive manner. The protein ATG7 is known to be essential for autophagy initiation by catalysing the lipidation of ATG8 proteins. Previously, we identified a short isoform, termed ATG7(2), which lacks 27 amino acids in the active domain of the protein, compared with the full-length ATG7(1), and is unable to lipidate ATG8 proteins. ATG7 is known to play a role in cancer progression and metastasis, and this role has long been associated with autophagy. However, recent studies suggest that this role could be, in part, autophagy-independent.

To understand the role of ATG7(2), we analysed clinical data from publicly available databases. This showed that high ATG7(2) expression is linked with poor prognosis in pancreatic adenocarcinoma (PAAD). Then, we quantified the mRNA expression of ATG7(1) and ATG7(2) in healthy versus cancerous pancreatic samples and observed an increase in the expression of both isoforms in the tumour samples. When analysing this in PAAD clinical stages, we observed increased ATG7(2) expression in Stage IV compared with other stages. Finally, our analysis revealed that immuno-active tumours express higher levels of ATG7(2) than immunologically quiet ones, across cancers.

Using CRISPR/Cas9 in a PAAD cell line, we selectively knocked out the canonical isoform ATG7(1) or total ATG7. We performed proliferation and migration assays on clones expressing different levels of endogenous ATG7(2). While total knock-out of ATG7 was linked with slow migration, ATG7(1)-/- showed faster proliferation and migration, especially with high levels of ATG7(2). Together, these results suggest that ATG7(2) could drive migration and proliferation in PAAD cells in an autophagy-independent manner.

Finally, we used siRNA to specifically knock down ATG7(2) in control and ATG7(1)-/- cells. This led to decreased migration and proliferation rates in both cell types compared with control siRNA. This project highlights the importance of ATG7(2) in cancer, and opens new avenues for therapeutic strategies.

About the doctoral candidate

Clémence Larat was born in 1997 in Gap, France. She completed a Master’s degree in Cancer Biology and a Master’s degree in Bioengineering at the University of Marseille in 2019. Clémence worked at Novartis in Switzerland for one year before beginning her doctoral studies at the Faculty of Medicine, University of Iceland, in the spring of 2022.