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Delineating epigenome regulators as functional survival dependencies in intrahepatic cholangiocarcinoma.

Project description

Epigenome regulators in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCC) is an aggressive cancer of the biliary tract with patient survival less than one year after diagnosis. Genomic analyses have identified mutations in epigenetic regulators associated with iCC. The EU-funded EPiCC project proposes to use patient-derived cell lines to characterise the functional role of key epigenetic regulators and the modifications linked to iCC chemotherapy resistance to identify new therapeutic targets. The specific aims of the project are the identification of iCC-associated functional epigenetic modifications using CRISPR/Cas9 technology and the characterisation of the epigenomic changes induced by the loss of the epigenetic regulators.

Objective

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.

Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 207 312,00
Address
NORREGADE 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 207 312,00