Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context

Abstract

Tumors cells reprogram their metabolism to fuel rapid growth. The ability to trace nutrient fluxes in the context of specific alterations has provided new mechanistic insight into the process of oncogenic transformation. A broad array of complementary genetic, epigenetic, transcriptional and translational mechanisms has been identified, revealing a metabolic landscape of cancer. However, cancer metabolism is not a static or uniform process, including within a single tumor. Tumor cells adapt to changing environmental conditions, profoundly shaping the enzymatic dependencies of individual cells. The underlying molecular mechanisms of adaptation, and the specific interactions between tumor genotype, oncogenic signaling, and tissue/biochemical context, remain incompletely understood. In this review, we examine dynamic aspects of how metabolic dependencies develop in cancer, shaped both by genotype and biochemical environment, and review how these interlaced processes generate targetable metabolic vulnerabilities. This article is part of a Special Issue entitled: Cancer Metabolism edited by Dr. Chi Van Dang.

Keywords: Cancer metabolism; Heterogeneity; Metabolic co-dependency; Oncogenic signaling; Tissue context; ecDNA.

Fig. 1. Oncogenic signaling reprograms metabolism of cancer cells to support rapid cell growth

PI3K-AKT-mTOR signal promotes glucose uptake, glycolysis and the flux of glucose carbon into fatty acids, lipid and nucleotides. Transcriptional factor MYC further enhances the glycolysis while also facilitates glutamine uptake and utilization, fatty acids, lipid and nucleotides de novo synthesis. Ras induces macropinocytosis as an alternative way of amino acids uptake. Filled green triangle target genes/pathways for PI3K; filed green circle target genes/pathways for AKT; filled green square target genes/ pathways for mTORC1; filled orange star target genes/pathways for MYC; filled pink triangle target process for Ras. GLUT1, Glucose transporter 1; MCT1, Monocarboxylate transporters 1; HK, Hexokinase; PKM, Pyruvate kinase; LDH, Lactate dehydrogenase; PDH, Pyruvate dehydrogenase; GDH, Glutamate dehydrogenase; GLS, Glutaminase; ACL, ATP citrate lyase; HMGCR, Hydroxymethylglutaryl-CoA reductase; ACC, Acetyl-CoA carboxylase; FASN, Fatty acid synthase; ASCT2, ASC amino acid transporter 2; G6P, Glucose 6-phosphate; 3PG, Glycerate 3-phosphate; PEP, Phosphoenolpyruvate; R5P, Ribose 5-phosphate; PPRP, Phosphoribosyl pyrophosphate; α-KG, α-ketoglutarate.

Fig. 2. Metabolic co-dependency of cancer cells shaped by environment and the interactions between environment, oncogenic signaling and genomic alternations

(A) Nutrient availability in the microenvironment determines metabolic dependencies of cancer cells. Cancer cells can synthesize proteins, lipids and nucleotides from different sources of nutrients, either through directly uptake from the environment or through synthesis from intermediate metabolites. (B) The interactions between environment, oncogenic signaling and genomic alternation, select favorable metabolic profiles and oncogenic signatures for tumor cells, contributing to tumor heterogeneity, tumor aggressiveness and therapeutic resistance. Metabolic stress from environment and oncogenic signaling influents DNA and histone modification of tumor cells. As a quick response, extrachromosomal DNA (ecDNA) profoundly contributes to accelerated tumor evolution and intratumoral genetic heterogeneity. Tumors also accumulate amplifications, mutations and deletions in their genome, which alters the metabolic and signaling profiles of cancer cells.

Fig. 3. Targeting metabolic co-dependency in cancer

(A) Mutations of SDHs and FH genes lead to accumulation of their individual substrates succinate and fumarate. Mutated IDHs acquire new function to convert α-KG into R-2-HG. These metabolites can inhibit α-KG dependent dioxygenases, and subsequently abolish HIF de-stabilization and DNA, histone demethylation. (B) When a metabolic gene recurrently co-amplified with a nearby oncogene, either in the form of chromosomal or extrachromosomal DNA, can drive the metabolic flux to a specific direction to aid malignant transformation, creating a metabolic co-dependency. Hitting co-amplified metabolic gene is a potential strategy to halt cancer cells. (C) Metabolic flux in normal cells comprises parallel or redundant pathways with feedback regulation mechanism, allowing metabolic plasticity. Metabolic gene co-deletion with a tumor suppressor impairs the plasticity, creating the potential to exploit synthetic lethality. (D) Oncogenes confer uncontrolled cell growth by providing sustained mitotic signal and reprogramming metabolism. Targeting reprogrammed metabolism becomes an alternative strategy when oncogene is not ideally druggable.