Epigenetic and Genetic interplay in Liver Cancer

Descripción del proyecto

Comprender el desarrollo tumoral del hepatocarcinoma

El hepatocarcinoma es una de las principales causas de mortalidad, pero aún se sabe poco sobre sus orígenes celulares. Aunque se conocen bien las alteraciones genéticas que lo desencadenan, aún no se ha estudiado cómo interactúan las mutaciones que favorecen su desarrollo y la erosión epigenética para aumentar la plasticidad celular. El proyecto EpiGen-LC, respaldado por las acciones Marie Skłodowska-Curie, tiene por objetivo identificar los principales factores de riesgo para favorecer el desarrollo de estrategias mejoradas de detección temprana del hepatocarcinoma. Los investigadores emplearán técnicas CRISPR para introducir mutaciones promotoras del cáncer en organoides obtenidos de tejido hepático sano y dañado. De este modo, se podrá estudiar cómo estas mutaciones inducen la remodelación epigenética y aumentan la plasticidad celular, así como la forma en que los cambios epigenéticos resultantes potencian, a su vez, la actividad promotora del cáncer.

Objetivo

Liver cancer is a leading cause of mortality worldwide, yet its cellular origins are poorly understood. The Valier lab (host) has shown that a population of hepatocyte-cholangiocyte bi-phenotypic cells expands during the progression of chronic liver disease (MASLD). Chronic injury leads to epigenetic erosion, which has been recognised as a cancer hallmark. Whilst genetic drivers of liver cancer have been identified, the capacity of epigenetic erosion and cancer-driver mutations to cooperate to drive cellular plasticity has not been explored. This fellowship will build on my expertise in somatic mutation acquisition in chronically inflamed tissues to: O1. Determine the capacity of liver cancer-driver mutations to promote epigenetic remodelling and cellular plasticity, and O2. Determine the capacity of epigenetic remodelling to drive cellular plasticity and enhance the function of liver cancer-driver mutations. The Vallier lab is uniquely positioned to host this project, having established protocols to derive and transdifferentiate human cholangiocyte and hepatocyte organoids. Using CRISPR, I will introduce cancer-driver mutations in organoids from healthy and epigenetically eroded end-stage liver disease tissue and evaluate the impact on plasticity between hepatocytes and cholangiocytes. This fellowship will give me expertise in liver biology, patient-derived organoids, genome engineering, epigenomic profiling, as well as bioinformatic skills. Communication and outreach will be supported by the international and translational environment of the BIH at Charité and the MPI-MG. I will acquire an interdisciplinary collaborative network and develop leadership skills under the mentorship of Prof. Dr. Vallier. By combining access to rare liver organoids with my background in mutation dynamics, the project will uncover early determinants of liver cancer that may inform strategies for early detection, and equip me to transition into an independent academic research career.