Project 2
Identification of selective metabolic vulnerabilities
A major activity of the division is the identification of metabolic vulnerabilities in cancer cells. Aerobic glycolysis, also known as the Warburg Effect, is a hallmark of cancer. Using functional genomic screening, we have shown that the monocarboxylate transporter (MCT4) is an essential regulator or metabolic activity and survival in breast cancer (Baenke et al., J Pathol 2015). Furthermore, we demonstrated that allosteric regulation of glycolysis by 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) promotes the balance between energy generation and anti-oxidant production to prevent oxidative stress and promote tumour growth in prostate cancer (Ros et al., Cancer Discovery 2012).
We also found that loss of the tumour suppressor TP53 increases the expression of PFKFB4 in colon cancer (Ros et al., Oncogene 2018). More recently, we demonstrated that liver cancer cells show a unique sensitivity towards aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma (HCC) cell lines. With a combination of metabolic flux analysis, metabolomics, stable isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase.
Targeting ALDOA effectively converted glycolysis from an energy producing into an energy consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells (Snaebjornsson et al. Nature Cancer 2025).
To explore the impact of different oncogenic drivers on cancer metabolism, we compared mouse models of liver cancer driven by activation of Akt or Nras together with Myc using transcriptomics, metabolomics and lipidomics analyses. This revealed a marked upregulation of lipid metabolism only in Akt-driven tumors, while Nras-activation was associated with an inflammatory signature. We conducted a direct in vivo screen of approx. 100 lipid metabolism genes in Akt- and Nras-driven liver tumors. This revealed several enzymes involved in acetyl-CoA metabolism as essential enzymes in Akt-driven liver cancer.