Descrizione del progetto
Il ruolo dell’infiammazione nel cancro
Da tempo viene sostenuta l’ipotesi che l’infiammazione cronica possa fungere da fattore di innesco per l’insorgenza del cancro. Prove recenti indicano che il fattore di crescita trasformante beta (TGF-b), una citochina presente negli stati infiammatori, influisce negativamente sull’integrità genomica attivando la transizione epiteliale-mesenchimale. Questa riprogrammazione epigenetica transitoria, fondamentale durante l’invasione tumorale e la formazione di metastasi, provoca instabilità cromosomica. Il progetto Onco-inflammation, finanziato dall’UE, concentra la sua attenzione sull’adenocarcinoma duttale pancreatico e intende definire i meccanismi infiammatori responsabili dell’induzione di instabilità genomica. I ricercatori del progetto ipotizzano che la riprogrammazione cellulare sia un fattore intermedio fondamentale per la creazione di instabilità genomica nel tessuto pancreatico, in modo analogo a quanto osservato nell’ambito della transizione epiteliale-mesenchimale. I risultati forniranno conoscenze fondamentali sull’associazione tra infiammazione e cancro.
Obiettivo
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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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
41092 Sevilla
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