Project description
The role of inflammation in cancer
It has long been speculated that chronic inflammation may serve as a trigger for cancer onset. Recent evidence indicates that the transforming growth factor beta (TGF-b) cytokine, observed in inflammatory states, negatively impacts genomic integrity by activating epithelial-to-mesenchymal-transition (EMT). This transient epigenetic reprogramming, key during tumour invasion and metastasis, leads to chromosomal instability. The EU-funded Onco-inflammation project focuses on pancreatic ductal adenocarcinoma and aims to delineate the inflammatory mechanisms responsible for inducing genomic instability. Project researchers hypothesise that cell reprogramming is a key intermediate in the creation of genomic instability in pancreatic tissue, similar to what is observed under EMT. Results will provide fundamental knowledge on the association between inflammation and cancer.
Objective
Inflammation is suspected to be the first step leading to cancer due to alcohol consumption or tobacco smoking between others. Little is known of how inflammation triggers genetic changes leading to tumorigenesis. Recently, 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. In view to understand how inflammatory signaling can affect the genome integrity, 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 will follow the establishment of genomic insults, and in particular focusing in whole genome doubling, nuclear envelope disruption and micronuclei. I will evaluate the genetic diversity present under pancreatitis and weigh the roles of the epigenetic re-programming Acinar-Dutual-Metaplasia as well as the oncogene KRAS, using high-resolution 3D imaging, as well as single cell CNV analysis (Aim1). I will also study the common pathways activated in newly aneuploid cells, in view to find some specific therapeutic target. (Aim2). Several pathways will be tested in an attempt to block cancer initiation and progression. Results will be tested and validated using human samples (Aim 3). At the Host Institution, I will greatly benefit and learn from the scientific guidance from my supervisor, expert in pancreas biology as well as experts in mitosis, genetic instability and bioinformatics. MSCA-IF will be instrumental to develop this initial hypothesis into deeper biological understanding the inflammation and cell plasticity’s roles on genomic instability and represent a crucial support to transition into an independent academic career.
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
41092 Sevilla
Spain