Origin of genomic instability: Understanding the biological influence of inflammation in the initiation of pancreatic tumorigenesis

Descripción del proyecto

La función de la inflamación en el cáncer

Durante mucho tiempo, se ha especulado que la inflamación crónica puede actuar como factor desencadenante de la aparición del cáncer. Pruebas recientes señalan que la citocina del factor de crecimiento transformante β, detectada en estados inflamatorios, afecta de manera negativa a la integridad genómica al activar la transición epitelial mesenquimatosa (TEM). Esta reprogramación epigenética transitoria, fundamental durante la invasión y la metástasis de las neoplasias malignas, conduce a la inestabilidad cromosómica. El objetivo del proyecto Onco-inflammation, financiado con fondos europeos, es estudiar el adenocarcinoma pancreático ductal y determinar los mecanismos inflamatorios responsables de la inestabilidad genómica. La hipótesis de sus investigadores es que la reprogramación celular funciona como un intermediario esencial de la inestabilidad genómica en el tejido pancreático, de forma parecida a lo observado en la TEM. Sus resultados proporcionarán conocimientos fundamentales sobre el vínculo entre la inflamación y el cáncer.

Objetivo

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.