Role of iron metabolism (dys)regulation in tumorigenesis: “IRONing out” cancer metabolism.

Cancer is being increasingly recognized as a metabolic disease. Cancer cells display profound metabolic alterations that enable them to meet the metabolic needs required for various aspects of malignancy, including proliferation. Understanding this metabolic rewiring is essential to decipher the fundamental mechanisms of tumorigenesis, as well as to find novel therapeutic solutions.

Iron is a trace element important for many cellular functions and like other metabolic pathways, iron homeostatic mechanisms are frequently altered in cancer (for a review see Torti and Torti, Nat. Rev. Cancer, 2013). Cellular iron metabolism is regulated by the iron regulatory proteins (IRP)-1 and -2, which coordinate the expression of various iron-metabolism proteins in the cell. We have generated conditional mouse models enabling the inactivation of IRP1, IRP2 or both proteins in a spatio-temporally controlled manner.

In this project, we  exploit those mouse lines together with well-established tumor models to determine how intrinsic misregulation of iron metabolism in cancer cells themselves and in microenvironment cells influences tumor biology, using histological and biochemical techniques, gene expression profiling, organoid cultures, etc. We  pay particular attention to cancers where inflammation plays an important role such as liver and intestinal cancers.

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Fundamental roles of Iron Regulatory Proteins: Why is iron metabolism regulation so important for life?

Cells need iron to proliferate and survive but not too much to avoid oxidative stress. Cellular iron metabolism is regulated by two conserved proteins called iron regulatory proteins (IRP)-1 and -2 (see above). The IRPs function as a rheostat: they sense cellular iron levels and in turn coordinate the expression of various iron-management proteins to restore adequate iron levels. To understand the role of the IRP regulatory network in cancer, it is essential to have a better understanding of its functions in normal cells. In this project we want to understand why the IRPs are so essential in some cell types, but no so much in other cell types. We are particularly interested in the precurssors cells that are present in the bone-marrow and give rise to our blood cells, as well as in cells that form the intestinal tract.

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Define the regulatory scope of Iron Regulatory Proteins: how many IRP targets are present in the transcriptome?

Iron metabolism is regulated by two RNA binding factors named iron regulatory proteins (IRP)-1 and -2, which interact with cis-regulatory stem-loop structures called iron responsive elements (IRE) and thereby modulate the translation or stability of target mRNAs. Our current knowledge of the IRP regulome is limited to a few IRE-containing genes that encode core iron metabolism molecules. Can all the biological functions of the IRPs be explained by modulation of iron metabolism, or do the IRPs have yet unknown targets?

In recent years, high-throughput approaches have been developed to explore posttranscriptional regulatory networks on a system-wide level. In this research proposal, we use a multi-omics approach to establish a comprehensive repertoire of IRP-target genes in cultured cells as well as in vivo in animal tissues.

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Establish an atlas of RNA-binding proteins active in tissues: How do cells shape their proteome?

UV cross-linking of RBPs to polyadenylated RNAs followed by stringent capture of the bound proteins with oligo-dT beads and identification by mass spectrometry has recently unraveled a full repertoire of RBPs active in various cultured cell lines. In collaboration with M. Hentze (EMBL) and J. Krijgsveld (DKFZ), we have adapted this technique to intact mouse tissues. We have been able to identify hundreds of known RBPs in mouse tissues, but also many proteins not previously known as RBPs. We use this approach to characterize in situ the mRNA-bound proteome of selected tumor samples. This approach will allow us to have a first snapshot of RBP signatures that hallmark certain types and/or stages of cancer. Through data mining and multi-evidence scoring, we plan to select top candidate RBPs potentially connected to cancer and explore their functions based on the expertise built for the study of the IRPs.

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