20092021

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Personal profile

Research interests

My research aims at understanding the biological relevance of non-coding RNAs in the human genome and how their deregulation is contributing to disease such as cancer. While 2% of the genome encodes for proteins, approximately 75% of the human genome is transcribed, potentially leading to the expression of various types of non-coding RNA (ncRNA). Long non-coding RNAs (LncRNAs) recently emerged as potent regulators of key cellular processes that are often deregulated in cancer. Because of their exceptional tissue and tumor-specificity, these regulatory RNAs represent promising targets for cancer therapy and might provide unique opportunities for disease monitoring through liquid biopsies.

 

On one hand, to globally assess the functional relevance of lncRNAs we have developed a strong expertise with CRISPR\Cas systems, which allows us to build comprehensive custom pooled guide RNA (gRNA) libraries and to perform large scale dropout screens in various cellular models. To establish and validate the potential of our screening platform, we first investigated if we could block the hyperactivation of the Wnt transcriptional program in colorectal cancer by silencing lncRNAs. Indeed, more than 80% of colorectal cancer patients have a mutation in APC or CTNNB1, which stabilizes β-catenin, induces the Wnt transcriptional program and promote tumor growth. Because of its central role in the transformation of intestinal stem cells, we then set-out to identify Wnt-regulated lncRNAs in CRC cell lines. To this end, we have profiled transcriptional changes upon β-catenin knockdown by using global run-on sequencing (GROseq). By profiling 15 CRC cell lines, we have globally identified Wnt-regulated lncRNAs and build a CRISPR inhibition (CRISPRi) custom pooled gRNA library to assess their biological relevance. Our screening efforts resulted in the identification of possibly more than 100 lncRNAs with an essential role for the expansion of CRC cells. The screening validation further reinforced the potential of our screening platform by uncovering a highly cancer-specific lncRNAs that can interfere with the Wnt pathway through the regulation of cMYC, a key β-catenin target gene and master regulator of the wnt program, and inhibit tumor growth in vivo. We have now established a collaboration with Alnylam pharmaceuticals (expert in RNAi-based therapy) to develop siRNA molecules able to target our lncRNA candidate and reduce tumor growth in vivo.

 

On the other hand, we are also evaluating the potential of using circulating lncRNAs for diagnostic purposes. We have formed a consortium with Rubina Baglio, an expert in extracellular vesicles at the VUmc, and the French company Firalis, which has a broad experience with biomarker discovery in liquid biopsies. We have investigated the presence of lncRNAs in circulating vesicles in healthy and CRC patients. This approach has uncovered several lncRNA molecules that are preferentially detected in cancer patients and we currently evaluate the possibility to use this information for the development of a diagnostic tool in CRC.

 

Having established our methodology, we are now aiming to expand our screening efforts to other oncogenic pathways as well as different cancer-types, and hope to uncover RNA molecules with high translational potential.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

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