Delineating epigenome regulators as functional survival dependencies in intrahepatic cholangiocarcinoma.

2026-07-22

Intrahepatic cholangiocarcinoma (iCC) is an aggressive malignancy of the biliary tract with escalating rates among both sexes in EU. Patients survive less than one year from diagnosis due to limited treatments and innate chemoresistance. Genomic analyses have identified recurrent mutations in epigenetic regulators in iCC. Malfunction of such genes has genome-wide consequences for epigenome-remodeling and transcriptome homeostasis, though this remains largely uncharacterized in iCC. Further, the extent to which iCC survival depends on these epigenetic alterations has not been determined. Clarification of these dependencies on epigenetic alterations, which unlike mutations are reversible, is crucial for the development of precision epigenome-targeted therapies for this aggressive disease. Using patient-derived cell lines (PDCLs), I propose to characterize iCC epigenetic survival dependencies to define the functional role(s) of key epigenetic regulators and ensuant epigenome remodeling, in turn identifying putative novel therapeutic targets. To achieve this, I have divided my EPiCC proposal in 2 specific aims: 1.Identify iCC-selective functional survival dependencies by state-of-the-art CRISPR/Cas9 screening. 2.Characterize the anti-neoplastic cellular and (epi)genomic consequences induced by the top epigenome regulator loss. Through integrating novel comprehensive approaches in iCC (CRISPR/Cas9 screening, R-loop mapping) with robust patient models (primary cells, omics from patient samples), I will provide novel insight into the epigenetic landscape of iCC and identify potential targets for future development of epigenetic-based precision medicine. This study will be supervised by Dr. Andersen, leading expert in the field of hepatobiliary cancers and translational genomics research. Therefore, EPiCC will provide me with new scientific expertise (both technical and transferable skills), a broader network and open new research avenues to follow up in my career.

Denmark

2026-02-15