Our main research objective is to understand the genomic, epigenomic, and metabolic changes leading to cancer in humans - and identify points of vulnerabilities that can be exploited for cancer therapy. We use various state-of-the-art genomic tools to interrogate tumor behavior, gene alterations and events that are fundamental to cancer development and survival.
We believe that the knowledge obtained on these cancer dependencies will allow us to design novel therapeutic approaches.
New research line 1: Enhancers.
Enhancers are non-coding genomic regions that activate gene expression of distantly located target genes. Interestingly, enhancer-binding genes were linked to cancer development, and novel cancer therapies block enhancer function. However, the human genome contains almost a million different enhancers while only few are potentially involved. To identify cancer-involved enhancers, the lab screened enhancer-targets of the tumor suppressor p53 or the Estrogen Receptor oncogene. This approach is yielding novel insights to the role of enhancers as tumor suppressors and oncogenes.
We also investigated the role of enhancer-associated RNAs (eRNAs). We show that p53-bound enhancers produce enhancer RNAs (eRNAs) that are required for enhancer activity.
Following the initial functional annotation of the identified enhancers, as well as the role of eRNAs, the group setup experiments to investigate relation to resistance to cancer therapy. We will use this information for cancer diagnosis and treatment.
New research line 2: mRNA translation.
In the past few years we established in the lab ribosome profiling technology to map with nucleotide precision ribosome position on mRNAs. with this technology we can study events regulated at the mRNA translation level. We have recently exploited this technology in the study of the tumor suppressor p53, translation in the mitochondria, and in response to oncogenic Myc activation.
New research line 3: Regulation of alternative polyadenylation.
Alternative cleavage and polyadenylation of mRNAs (APA) is emerging as an important layer of gene regulation as the majority of mammalian genes were already demonstrated to contain multiple polyadenylation (poly(A) sites in their 3' UnTranslated Regions (3’UTRs). Significant change in APA is observed when cells were stimulated to proliferate, differentiate, and during cancer progression. We uncovered the role of in APA and link it with a human genetic disorder.
Past research line 4: Interplay between miRNAs and RBPs.
Interestingly, we noticed that the regions surrounding some functional miRNA targets (identified by our genetic screens) are highly conserved throughout evolution. We hypothesized that these regions recruit RNA binding proteins (RBPs) that regulate miRNA function. We performed genetic screens and identified and characterized RBPs that can inhibit or potentiate the accessibility of miRNAs to their target mRNAs. We suggest that the genetic interaction between miRNAs and RBPs influence developmental processes, cellular proliferation, and cancer.
Past research line 5: Functional screens for cancerous miRNAs.
In the past years we initiated studies to identify cancerous microRNAs (miRNAs), a newly emerging gene family encoding for endogenous small RNAs. We developed and are still using novel and unique genetic approaches to screen for cancer-causing and cancer-preventing miRNAs.
Past research line 6: Functional screens using RNAi.
Most human tumors harbor multiple genetic alterations that activate oncogenes, inhibit tumor suppressors and induce genomic instability. As each tumor contains many genetic alterations, the study of the contribution of each alteration to the cancerous phenotype was obscured. In the past, we developed and successfully used an RNA interference (RNAi) approach to inactivate genes in mammalian cells. We used this RNAi system to characterize tumor suppressors and novel components of DNA damage signaling components.
The group 2014