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H2020Individual fellowship2016–2018

EpiLIVER · Characterization and implications of DNA damage response in liver cancer

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-01-01 → 2018-01-14
EU contribution
€200,195
Participants
1
Scheme
MSCA-IF-EF-ST

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Results in brief

Characterization and implications of DNA damage response in liver cancer

Cholangiocarcinoma (CCA) is the most lethal type of liver cancer, with no approved treatment to date. Despite it dismal prognosis, there is limited understanding about the molecular mechanisms underlying the development of the disease. Most publications have focused on a genetic and epigenetic overall landscape of the disease, with some potential exploratory areas. For instance, despite its very heterogeneous nature, inactivating mutations on the SWI/SNF complex have shown to be associated with roughly 47% of all CCA case. This multimeric complex is crucial for proper DNA damage response (DDR) and repair and consequently, genomic stability. To that end, herein we investigated the role of the SWI/SNF complex on the maintenance of CCA, with the overall objectives: 1. Identify the most relevant subunits of SWI/SNF associated to CCA; 2. Characterize target candidates in the context of homologous recombination (HR) repair; and 3. Profiling of chromatin proteome dynamics in CCA. Given the fact that CCA is one of the few types of cancer with a steady and alarming increase for the last decades in EU, coupled with its poor diagnostic feature and relatively high mortality rate, we seek to provide in insight onto potential targets for proper diagnosis and therapy. Furthermore, the SWI/SNF complex is a key epigenetic regulator. Epigenetic therapy holds a promising alternative to conventional treatments, due to its ubiquitous role in DNA regulation without the need for genetic alterations. Finally, Denmark is currently a hotbed for Biotech companies, of which many of those are based on epigenetic treatment.

Data: CORDIS, © European Union

Project objective

Cholangiocarcinoma (CCA) is a devastating type of liver cancer that presents late, is difficult to diagnose and associated with a high mortality. Although worldwide the epidemiological trend is mixed, in the EU it has been steadily increasing for the last decade. Treatment is limited to tumor resection, which is not applicable in the vast majority of cases. The lack of any approved chemotherapy-based treatment is partially due to the poor understanding of the molecular mechanisms involved in the response to these drugs. Taking advantage of the comprehensive panel of established and primary CCA cell lines in the host PI’s lab and my expertise on the DNA damage response (DDR) and repair field, my proposal offers a new approach in this scenario by characterizing the DDR of CCA cells. This study will be focused on the DDR-related chromatin remodeling SWI/SNF complex. In recent works, mutations in this family of proteins were identified in 47% of all CCA cases analyzed through whole exome sequencing, hence providing a relevant rationale in studying this complex. First, I will identify candidate markers of all known components of the SWI/SNF complex, based on RNAi high-throughput analysis. I will then perform direct and quantitative measurements of the DNA repair activity in CCA cells, specifically related to homologous recombination repair (HR) by rapid and sensitive reporter assays. And lastly, I will determine the proteome dynamics in the CCA context. There are two exclusive novelties on this approach: (1) the described novel methods will be employed in the Hepatology field for the first time; and (2) the use of primary CCA cells will enable me to directly compare observations in culture with clinical outcome. This proposal will not only contribute to the understanding of a limited understood area in liver cancer, but also holds great promises for future clinical use, where DDR-based drugs are the clinical mainstay

Original text from CORDIS.

Participants

  • KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark

Links

Data: CORDIS, © European Union