Metabolic Alterations: The Achilles’ Heel of Cancer Cells?

Key words: cancer therapy, transformation mechanisms, tumor cell metabolism, hypoxia, tumor viruses, human papillomaviruses (HPV), senescence, apoptosis, signal transduction

Compared to normal cells, cancer cells typically exhibit metabolic changes which support their malignant growth. Exploring tumor cell-specific metabolic alterations may ultimately enable the development of novel, rational strategies for cancer therapy. In this context, we are particularly interested in human papillomavirus (HPV)-induced cancers which cause a significant portion of the cancer burden worldwide, including cervical cancer and head & neck cancer (HNSCC) (Hoppe-Seyler et al., 2018).

1. Metabolic Drugs

We investigate the phenotypic effects and therapeutic potential of metabolic drugs, such as the antifungal agent Ciclopirox, an iron chelator, or the antidiabetic agent Metformin, an inhibitor of oxidative phosphorylation. Both drugs efficiently block HPV oncogene expression and modulate the apoptosis and senescence response in HPV-positive tumor cells, also in response to chemo- and radiotherapy (Braun et al., 2020; Hoppe-Seyler, Herrmann et al., 2021).

Moreover, we have recently identified a metabolic switch which can efficiently block the pro-tumorigenic STAT3 signal transduction cascade. Ongoing work aims to elucidate the mechanism of STAT3 inhibition and the resulting phenotypic consequences in cancer cells.

2. Chronic and Cycling Hypoxia

Many solid tumors contain regions of low oxygen concentrations ("hypoxia"). Hypoxia critically determines the clinical behaviour of cancers and is typically linked to increased therapeutic resistance against chemo- and radiotherapy (Hoppe-Seyler et al., 2017a). We are very much interested to functionally study the role of hypoxia for the malignant phenotype and the therapeutic resistance of cancer cells.

We uncovered that HPV-positive cancer cells exposed to chronic hypoxia induce a state of dormancy characterized by viral oncogene repression and a reversible growth arrest, which could contribute to therapy resistance, immune evasion and tumor recurrency (Hoppe-Seyler et al., 2017b) (Press release DKFZ). Mechanistically, we identified the PI3K/AKT signaling cascade as being critical for mediating the hypoxic repression of the HPV oncogenes (Bossler et al., 2019).

Ongoing studies are extended to a second major form of hypoxia in cancers, named cycling hypoxia (Hoppe-Seyler et al., 2017a), which may be particularly important for the malignant growth and the therapeutic resistance of tumor cells.

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Chronic and cycling hypoxia. (A) Diffusion-limited chronic hypoxia, e.g., due to enlarged distances between tumor blood vessels and tumor cells. Remote tumor cells are inadequately supplied with O2 and become hypoxic. Red: oyxgenated tumor cells, blue: hypoxic tumor cells. (B) Perfusion-limited cycling hypoxia. Tumor vessels are often abnormally structured and can be temporarily occluded, e.g., through blood cell aggregates. Surrounding tumor cells will be exposed to fluctuating cycles of physoxia (left) or hypoxia (right). (Adapted from Hoppe-Seyler et al., 2017a).

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

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