Defining a metabolic landscape of tumours: genome meets metabolism

Abstract

Cancer is a complex disease of multiple alterations occuring at the epigenomic, genomic, transcriptomic, proteomic and/or metabolic levels. The contribution of genetic mutations in cancer initiation, progression and evolution is well understood. However, although metabolic changes in cancer have long been acknowledged and considered a plausible therapeutic target, the crosstalk between genetic and metabolic alterations throughout cancer types is not clearly defined. In this review, we summarise the present understanding of the interactions between genetic drivers of cellular transformation and cancer-associated metabolic changes, and how these interactions contribute to metabolic heterogeneity of tumours. We discuss the essential question of whether changes in metabolism are a cause or a consequence in the formation of cancer. We highlight two modes of how metabolism contributes to tumour formation. One is when metabolic reprogramming occurs downstream of oncogenic mutations in signalling pathways and supports tumorigenesis. The other is where metabolic reprogramming initiates transformation being either downstream of mutations in oncometabolite genes or induced by chronic wounding, inflammation, oxygen stress or metabolic diseases. Finally, we focus on the factors that can contribute to metabolic heterogeneity in tumours, including genetic heterogeneity, immunomodulatory factors and tissue architecture. We believe that an in-depth understanding of cancer metabolic reprogramming, and the role of metabolic dysregulation in tumour initiation and progression, can help identify cellular vulnerabilities that can be exploited for therapeutic use.

Fig. 1

Schematic diagram of the metabolic nodes of tumour initiation and their directional regulation in defining a cancer cell state and metabolic landscape in cancer. a Genetic alterations in oncogenes, tumour suppressors and oncometabolite genes can lead to metabolic reprogramming. Alternatively, metabolic dysregulation can be an initiator of cellular transformation. Tumour-initiating nodes in the cancer cell regulatory network are highlighted in red. b Visual depiction of the regulatory network defining the cancer cell state. Oncometabolite genes are highlighted in orange boxes.

Fig. 2

Drivers and contributors of metabolic heterogeneity in cancer. a Gradients of regulatory factors in a tumour microenvironment. b Global view of a tumour depicting zonation pattern, with the core being most hypoxic, enveloped by a quiescent zone, and margins being proliferative and in continuous interaction with the stroma, vasculature, immune cells (lymphocytes like T cells, B cells and NK cells; monocytes like macrophages or dendritic cells), cancer-associated fibroblasts (CAFs) and host tissue matrix. c Regional view of a tumour depicting interaction between multiple zones of hypoxia, vasculature and inflammation, with immune cells in continuous interaction within the tissue matrix. Apart from metabolic factors, genetic clonal heterogeneity is also shown. For panels b and c, Inflammation is shown by immune cells as represented by lymphocytes (shown as dark irregular green circles) and monocytes (shown as blue stars). Tumour vasculature is shown in red. Clones A, B, C, D and E (shown in navy blue, pastel green, yellow, light blue and pink colour solid circles, respectively) represent multiple cancer cell clonal populations formed by genetic alterations in the same tumour. Cancer stem cells are shown as dark brown circles. Zonation of tumour for Clone C is shown in hues of brown colour, with the darkest zone depicting the most hypoxic and nutrient-starved region. Cells shown with elongated phenotype represent cancer-associated fibroblasts (shown in lavender colour). Stromal cells in tumour microenvironment are shown as brown-coloured elongated cells.