Research group Metabolism of Infection- and Inflammation-induced Cancer

Figure 1: Dietary iron is taken up by duodenal enterocytes, exported into the circulation via the iron exporter ferroportin (FPN), and loaded onto transferrin. Transferrin-bound iron is then distributed to tissues and is largely used for heme synthesis in red blood cells. Tissue macrophages recycle iron from effete erythrocytes and export it back into the circulation via FPN. The non-used iron is stored in hepatocytes. The hepatic hormone hepcidin lowers plasma iron levels by inhibiting the FPN iron exporter present at the surface of enterocytes and macrophages. Hepcidin synthesis is in turn regulated by plasma iron levels.
© dkfz.de

Research theme…

Malignant tumor cells exhibit different metabolic requirements compared to most normal differentiated cells. Because such alterations can promote tumor initiation and metastatic progression, targeting the specific metabolic needs of cancer cells may be of therapeutic value. It is therefore of utmost importance to better understand the molecular bases that underlie metabolic reprogramming in cancer. Our lab investigates the molecular bases that underlie metabolic reprogramming in cancer, with a focus on posttranscriptional mechanisms. We use iron metabolism and its (dys)regulation as a main model system.

 

Both iron deficiency and excess are detrimental…

Alterations in iron metabolism are emerging as a key metabolic “hallmark of cancer”. The metal helps cells to proliferate, and intrinsic alterations in cancer cells tend to enhance cellular iron availability while microenvironment cells are programmed to fuel cancerous cells with iron. When present in excess, iron also promotes the generation of free radicals, which cause DNA lesions and produce an inflammatory environment favouring tumor formation. This could explain in part why iron loading promotes hepatocarcinogenesis in hepatitis C virus infection, for example. On the other hand, iron is required for maintaining genome integrity; it also mediates ferroptotic cell death in response to specific anticancer compounds. The role of iron in cancer is thus complex and subtle changes in the iron balance in cancer versus surrounding cells influence tumor initiation, progression and treatment in multiple ways.

Figure 2: In iron-deficient cells, both IRPs bind to the 5’untranslated region (UTR) IRE of the ferritin H- and L-chain mRNAs to inhibit their translation and thus decrease iron sequestration, while their binding to the 3’UTR IREs of the transferrin receptor 1 (TFR1) mRNA prevents its degradation and increases cellular iron uptake. In turn, iron repletion decreases IRE-binding via iron-sulfur cluster assembly on IRP1, causing its conversion to a cytosolic aconitase, and iron-targeted degradation of IRP2. Additional IRP-target mRNAs identified so far encode the FPN exporter, the DMT1 iron uptake molecule, as well as proteins involved in energy metabolism (ACO2), heme synthesis (ALAS2) and response to hypoxia (HIF2alpha).
© dkfz.de

How to achieve iron homeostasis…

In mammals, iron metabolism is balanced by two major regulatory systems:

  • One controls systemic iron fluxes and relies on the liver hormone hepcidin and its receptor ferroportin (FPN) (Fig. 1).
     
  • The other orchestrates cellular iron metabolism through iron-regulatory proteins (IRP)-1 and -2, two proteins that bind cis-regulatory iron-responsive elements (IRE) present in mRNAs encoding iron management proteins (Fig. 2).

 

Our lab will use state-of-the-art cellular and animal models to investigate the role(s) of these central iron regulatory networks in infection and inflammation-induced tumor formation. One focus will be on liver cancer, which is frequently linked to infection with hepatitis B or hepatitis C virus and thus represents a paradigm of pathogen- and inflammation-induced carcinogenesis. In the long run we will also exploit the tools and approaches developed for the study of iron metabolism to investigate other metabolic regulatory networks important for cancer.

Current projects

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

under construction

 

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

under construction

 

III-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 study IRP biology in vivo, we have generated mouse lines with conditional loss of function Irp alleles.

In this project we study the role of the IRPs in normal physiology. 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.

 

IV-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). Iron metabolism is regulated by a iron regulatory proteins (IRP)-1 and -2, which coordinate the expression of various iron-management proteins in the cell (see above). By targeting the IRP gene regulatory network, we have been able to generate mouse lines that offer the possibility to disrupt iron homeostasis in any cell type of interest in vivo.

In this project, we will 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 will pay particular attention to cancers where inflammation plays an important role such as liver and intestinal cancers.

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