Inflammation is suspected to be the first step leading to cancer due to alcohol consumption, tobacco smoking or air pollution between others. Little is known of how inflammation triggers genetic changes leading to tumorigenesis. In previous work I show that TGFb, a cytokine present during inflammation, is able to generate aneuploidy, polyploidy and plausible chromosomal rearrangements in breast cells. Such effects were mediated through the induction of the epigenetic reprogramming EMT, highlighting the effect of cellular plasticity in the generation of genomic variability. Then, in view to understand how inflammatory signaling can affect the genome integrity in vivo, I design the project Onco-Inflammation, to study one of the most lethal cancer, the pancreatic ductal adenocarcinoma (PDAC), where therapeutic options are greatly limited. Using several mice models of pancreatitis, we follow the establishment of genomic insults, and in particular focusing on the role of the epigenetic re-programming Acinar-Ductal-Metaplasia as well as the oncogene KRAS, primordial for tissue regeneration through cellular plasticity. We want to focus in particular in events such as whole genome doubling, nuclear envelope disruption and micronuclei.
By understanding the mechanisms behind the initiation of tumorigenesis, new therapeutic targets and early detection markers can be discovered, which are really needed to improve the diagnostic and prognostic of those patients.
The overall objective of this grant is to understand better the link better cellular plasticity, inflammation and genomic changes in an attempt to find new cures. During this grant, we develop this initial hypothesis into deeper biological understanding of the inflammation and cell plasticity’s roles on genomic instability. A parallel goal of the MSCA Individual Fellowship is to foster the development of the individual researcher. The results from this grant represent a crucial support to transition into an independent academic career.
