Research

1.) Cancer-Linked HPVs and the Host Cell Metabolism

Cancer cells exhibit metabolic alterations which are crucial for their malignant growth. Exploring tumor cell-specific metabolic alterations may identify an “Achilles’ heel” of cancer and ultimately enable the development of novel strategies for cancer therapy.

Tumor viruses, such as oncogenic human papillomaviruses (HPVs), are important human carcinogens. Interestingly, there is relatively little known about the possible interactions between oncogenic HPVs and the host cell metabolism (Hoppe-Seyler et al., 2018).

Therefore, we are interested in answering two major questions (Fig. 1):
(i) Do tumor viruses lead to cancer by manipulating the host cell metabolism and
(ii) does the metabolic state of the host cell affect the activity of tumor viruses?

 

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Fig. 1. We study the crosstalk between tumor viruses (oncogenic HPVs) and the metabolism of their host cell, focusing on the role of oxygen (O2) supply, and on iron (Fe) and glucose (Gluc) metabolism.

 

We concentrate on three metabolic systems which are typically affected in tumor cells:

a) Hypoxia
Many cancers, including HPV-positive cancers, contain regions of low oxygen (O2) content („hypoxia“). This determines their clinical behaviour, in that hypoxic tumors often exhibit a poor prognosis and increased therapeutic resistance (Hoppe-Seyler et al., 2017a). We investigate the effects of HPVs on cellular factors involved in the response to hypoxia and, vice versa, the influence of O2 supply on the HPV oncogenes.
We found that HPV-positive cancer cells exposed to chronic hypoxia induce a dormant state, characterized by repression of the viral oncogenes and a growth arrest which is reverted by re-oxgenation. This regulation could contribute to therapy resistance, immune evasion and tumor recurrency (Hoppe-Seyler et al., 2017b) (Press release DKFZ). Mechanistically, our recent studies identified the PI3K/AKT signaling cascade as being critical for mediating the hypoxic repression of the HPV oncogenes (Bossler et al., 2019).
Ongoing studies analyze selected cellular proteins which are hypoxia-responsive, as assessed by proteome analyses (Bossler et al., 2019), and which may be involved in carcinogenesis and therapy resistance of tumors.

b) Iron Metabolism
The proliferation and survival of tumor cells can profit from an increased intracellular iron availability. We study the effect of HPVs on key regulators of iron metabolism, and the influence of intracellular iron availability on the expression and function of the HPV oncogenes. Moreover, we investigate the therapeutic potential of iron chelators as anticancer agents.

c) Glucose Metabolism
Tumor cells typically exhibit an increased rate of aerobic glycoloysis (“Warburg effect”) for the generation of energy (ATP) and intermediates for tumor cell growth (nucleic acid precursors, lipids) from glucose. We study whether the HPV oncogenes may affect this tumor-linked metabolic process (Hoppe-Seyler et al., 2017c).

d) Metabolic Modulators as Future Drugs
Since tumor cells typically reprogram their metabolism, they differ in their metabolic regulation from normal cells. This could provide unique opportunities to develop novel therapeutic strategies which preferentially attack tumor cells. We therefore also investigate compounds/drugs which target specific biochemical pathways in cancer cells, with the overall aim to provide novel options for tumor therapy.

2) Identification of Cellular Targets for Oncogenic HPVs

We have identified cellular genes (e.g. BTG2, EZH2, LEDGF) which are deregulated by the oncogenic  HPVs. For example, we found that the cellular LEDGF gene is activated by the HPV oncogenes (Leitz et al., 2014) and protects tumor cells against radio- and chemotherapy. Thus, LEDGF could play a major role for the therapeutic resistance of tumors in the clinic (Press release DKFZ).

Furthermore, we found that the HPV E6/E7 oncogenes induce profound alterations of the intracellular miRNA network, increasing the amounts of pro-tumorigenic and decreasing the amounts of anti-tumorigenic miRNAs (Honegger et al., 2015). This indicates that the deregulation of miRNAs by HPVs may contribute to viral oncogenesis and raises the possibility that the correction of HPV-induced miRNA alterations could possess therapeutic potential. We also uncovered that the viral oncogenes strongly affect the miRNA composition of exosomes which can serve as intercellular shuttles for cell-to-cell communication (Honegger et al., 2013).

Ongoing work analyzes additional cellular genes targeted by the viral E6/E7 oncogenes, studying their role for HPV-linked carcinogenesis and the therapeutic resistance of HPV-positive cancer cells.

Our work is supported by the Wilhelm Sander-Stiftung and by the Deutsche Krebshilfe.

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