Can viral infection of the lower respiratory tract promote lung cancer via the dysregulation of the innate immune effector APOBEC3?

Project: Research

Project Details


After the spontaneous mutations linked with aging, the second most
frequent type of mutations observed in cancer genomes is attributed to the
APOBEC3 enzymes (Apolipoprotein B Editing Catalytic subunits 3 or A3s).
A3s are normal components of the innate immune system restricting viruses
and retroelements by cytidine deamination. The goal of this project is to
understand the chain of events leading to the APOBEC3 mutational
signature in cancer. We will focus on lung cancer as a large proportion of
these tumors display A3-induced mutations. There are several outstanding
questions about A3 mutagenicity. i. What are the events inducing A3
expression? A3 mutagenesis in head and neck squamous cell carcinomas
has been linked with human papilloma virus infection. We will test whether a
lung viral infection can trigger A3-associated mutations. ii. What are the
conditions making A3 expression potentially mutagenic? A3 substrate’s is
single-stranded DNA, a species that is notably present during DNA repair.
We will test whether DNA damaging agents, like the cigarette smoke
carcinogenic compounds, can synergize with viral infection to promote A3-
associated mutations. iii. Are human A3s oncogenic in mouse models? We
will evaluate human A3s mutagenic activity in mice. We will notably
combine heterologous A3 expression with carcinogen exposure to test
whether these chemicals can potentiate A3 mutagenesis. Since A3s could
initiate tumor development and favor metastasis and drug-resistance at
advanced stages by subclonal diversification, understanding their
expression and mutagenic activity mechanisms would help to develop new
therapies supporting those existing.
Short titleAdenoviruses, APOBEC3 and lung cancer
Effective start/end date1/10/1731/12/19

Attachment to an Research Institute in UNAMUR



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