Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism

Abstract

Metabolic transformation is a hallmark of cancer and a critical target for cancer therapy. Cancer metabolism and behaviour are regulated by cell-intrinsic factors as well as metabolite availability in the tumour microenvironment (TME). This metabolic niche within the TME is shaped by four tiers of regulation: (1) intrinsic tumour cell metabolism, (2) interactions between cancer cells and non-cancerous cells, (3) tumour location and heterogeneity and (4) whole-body metabolic homeostasis. Here, we define these modes of metabolic regulation and review how distinct cell types contribute to the metabolite composition of the TME. Finally, we connect these insights to understand how each of these tiers offers unique therapeutic potential to modulate the metabolic profile and function of all cells inhabiting the TME.

Figure 1.. Schematic representation of the metabolic fluctuations/niches that influence the metabolite composition of the TME

The metabolite composition of the TME is determined by different levels of regulation. Primarily, the local nutrient availability is defined by tumor cell metabolism and through the metabolic cross-talk of tumor cells, infiltrating immune cells and supporting stromal cells. All these cell types change the TME through the consumption and secretion of metabolites, and are influenced by the resulting conditions. Nevertheless, the metabolic microenvironment is also determined by the anatomical location of the tumor. Metabolite heterogeneity has been found in different organs and even in sublocal organ and tumor locations, due to tissue structure, levels of perfusion and function. Lastly, differences in metabolite availability can also arise from a change in systemic metabolism. This could be dietary interventions, function of the metabolic organs or metabolic syndromes. Although each of these levels contribute to the heterogeneity of the TME, they all possess specific therapeutic potential.

Figure 2.. Tumor metabolism influences and is influenced by the metabolite composition of the TME

Tumor cells have been shown to adapt to the TME and to take advantage of local metabolite compositions in order to sustain tumor growth, proliferation and survival. Aside from the well-studied Warburg effect, tumor cells also recycle waste products such as ammonia and lactate in order to sustain biomass production. Furthermore, specifically in vivo, low levels of cystine reduce the activity of the antiporter xCT/SLC7A11 and thus glutamate export. The high intracellular glutamate pool limits glutamine catabolism and anaplerosis. Finally, high uric adic levels in the plasma inhibit UMP synthase (UMPS) and pyrimidine synthesis.

Figure 3.. The metabolic cross-talk between tumor cells and immune or stromal cells within the TME

The metabolite composition of the TME is shaped by stromal and immune cells, each with unique metabolic profiles, dependencies, and vulnerabilities compared to tumor cells. Here we depict the metabolic interactions of T cells (blue), macrophages (red) or stromal cells (green) with tumor cells (brown) in the TME. Yellow arrows indicate upregulation.

Figure 4.. Inter-organ and intra-tumor microenvironments define the metabolic properties of tumor cells

Left panel: while breast primary tumors rely on glucose and glutamine metabolism, metastatic tumors use pyruvate (lung metastasis), serine and acetate (brain metastasis) to sustain the TCA cycle. Right panel: within the same organ, a tumor can develop at different sites. The level of perfusion can dictate metabolic activity of tumor cells. Indeed, lung cancer cells in highly perfused areas consume glucose to sustain both glycolysis and OXPHOS, while cancer cells in lowly perfused areas rely on other carbon sources. Yellow arrows indicate upregulation.