RESEARCH ACTIVITY

One leading project of the Indraccolo lab will be presented here.

METABOLIC ADAPTATION OF TUMORS TO ANTI-ANGIOGENIC THERAPY
The focus of our research is to investigate metabolic heterogeneity of tumors and how this modulates and is itself modulated by anti-angiogenic therapy. In this conceptual framework, we are also keen to investigate the possible impact on tumor angiogenesis of therapeutic strategies targeting glycolysis and their combination with anti-angiogenic therapy.
Background
Albeit less studied compared with genetic heterogeneity, it is increasingly recognized that tumors are metabolically heterogeneous. In general, both inter-tumor and intra-tumor metabolic heterogeneity can be observed and the biological basis of this phenomenon remains largely unexplored. Enhanced glycolytic activity, one of the best known metabolic hallmarks of cancer, is an heterogeneous trait of tumors and is inter-connected with another hallmark of cancer, namely angiogenesis. Indeed, it has been shown that soluble factors released by highly glycolytic tumor cells, such as lactic acid, modulate the stromal microenvironment, contributing to promote angiogenesis. On the other hand, it has also been observed that endothelial cells preferentially use glycolysis as energy source, especially during angiogenesis. Therefore, in the presence of highly glycolytic tumor cells a metabolic competition with endothelial cells could occur, and glucose could become a limiting substrate for angiogenesis. This provisional balance between two seemingly opposing forces could be further perturbed by anti-angiogenic therapies, which hit the microvasculature and simultaneously increase tumor glycolysis. These mechanisms could underscore modulation of the therapeutic activity of anti-angiogenic drugs by a tumor metabolic trait.
Research achievements
Our team pioneered investigation of metabolic effects of anti-angiogenic drugs in solid tumors. We initially established that VEGF blockade is accompanied by dramatic reduction in glucose and ATP levels in the tumor microenvironment (Nardo G. et al. Cancer Res 2011) and this metabolic change activates the LKB1/AMPK pathway, a sensor of nutrients starvation in cells. We further hypothesized that alterations affecting this pathway could modulate therapeutic response to anti-VEGF drugs, and validated this hypothesis in CRC and lung cancer patients treated with chemotherapy plus bevacizumab (Zulato E. et al., BJC 2014 and Bonanno L. et al., CCR 2017). In parallel, we found that anti-VEGF therapy impacts on the metabolic profile of tumors and exacerbates the Warburg phenotype of tumors. Importantly, some of these metabolic changes are stable and are associated with resistance to bevacizumab (Curtarello M. et al. Cancer Res 2015). Additional metabolic changes occurring in tumors treated with angiogenesis inhibitors are currently under investigation in collaboration with other groups (Curtarello M. et al., Cells 2019).
Conclusions and perspectives
Results of our ongoing studies will provide a multi-level representation of the connections between the glycolytic phenotype of tumors and certain genetic or epigenetic profiles, highlight the therapeutic potential of glycolysis inhibitors in combination with anti-angiogenic drugs, investigate effects of tumor glycolysis on angiogenesis, and establish the possible predictive value of metabolic markers in patients treated with anti-angiogenic drugs.