From Systemic Lupus Erythematosus to Cancer: role of the Mutator Enzyme APOBEC3A in auto-immunity and tumorigenesis

Purpose : I propose to join the laboratory of Prof. Simon Wain-Hobson at Institut Pasteur, Paris toinvestigate the role of APOBEC3A in chronic inflammation and tumorigenesis, using Systemic Lupus Erythematosus (SLE) as a model.
Background : APOBEC3 (A3) are a family of mutator enzymes which restrict retroviruses and retro elementsby massively deaminating cytidine (C) into uridine (U) on single stranded DNA. Uridine in DNA is either excised, leading to DNA breaks and apoptosis, or paired to Adenine (A) on the complementary strand,leading to C>T mutations (and G>A on the opposite strand). Too high a mutation burden is lethal to the invading pathogen. This potent antiviral response, however, comes at the expense of collateral damage to cellular DNA: A3A and A3B can enter the nucleus and edit chromosomal DNA. Notwithstanding, the most common mutations in cancer genomes are C>T (and G>A ) transitions where C is preceded by T and followed by A or T (TpCpW) a signature of editing by A3A or A3B. A3A and A3B have been shown to increase the mutational burden in a number of cancers.
Cancer development is a decade-long, multifactorial process characterized by DNA damage (translocations, duplications, somatic mutations). It frequently occurs on a background of chronic inflammation. Interferon (IFN)-I and Interferon-Stimulated Genes (ISGs) are major effectors of the inflammatory response. A3A is an ISG. Therefore, I hypothesize that A3A is upregulated in chronic inflammatory conditions.
Work hypothesis : I propose to investigate the role of A3A as a keystone bridging chronic inflammation,DNA damage and tumorigenesis, using SLE as a model. SLE is a chronic auto-immune inflammatory condition characterized by DNA circulating in plasma and antibodies against DNA. Haematological and solid malignancies such as invasive cervical cancer, are higher among SLE patients. I will couple ex vivo patient sample analyses and in vitro set-ups, to answer the following questions:
a.Is A3A upregulated in SLE? In which cellular subsets?
b.Does A3A edit SLE genomes, favoring cell immortalization and growth?
c.Does oxidative stress induce A3A?
d.Is there a relationship between A3A and DNA sensing pathways induced by IFN-I, such as cGAS-STING?
Scientific relevance : Answers to these questions likely extend beyond SLE to chronic inflammatory,autoimmune and viral conditions. Deciphering molecular pathways that contribute to cell transformation is key to the early interception of oncogenesis as it provides new targets for intervention and biomarkers for personalized medicine.
Strategic relevance : The strategic rearrangements of the Department of Infection and Immunity (DII) and my co-heading of the Molecular Signalling and Virus Host interactions Team with Dr. Andy Chevigné have prompted me to extend my research beyond HIV and to develop a research line coherent with our Team’sand Department’s visions. This study on SLE is the first building block of a broader research line on the molecular links between chronic viral infections (HPV, herpes viruses) and virus-related tumorigenesis - the cause of 20% of cancers. I will focus viral triggers of A3 through the mitochondrion, on the molecular pathways they intercept and affect, as well as in their role in shaping immune responses through mutagenesis. This research thematic is the converging point of my prior experience in HIV and of my current experience in the molecular bases of chronic interferonopathies. It will also lay the grounds for collaborative projects with other groups within DII and in Luxembourg, and of course, with the Wain-Hobson laboratory, possibly through Junior CORE and CORE/INTER applications. The knowledge and know-how acquired in the Wain-Hobson laboratory will be seminal to rapidly implement this research in DII, to set precedence in the field in terms of background, publications, network and reputation in the field.