The metabolism of cancer cells during metastasis

Abstract

Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.

Figures

Fig. 1 |. Metabolite plasticity and flexibility in metastasizing cancer cells.

Metastasizing cells undergo dynamic metabolic changes to adjust to the differing microenvironments while travelling to distant organs. Thereby, metastasizing cells can exhibit metabolic plasticity in which they use one metabolite to fuel the various metabolic requirements of the different steps in the metastatic cascade. Alternatively, they can display nutrient flexibility by using multiple metabolites to meet the same metabolic requirement imposed by a specific step of the metastatic cascade. In cancer cells, both phenomena, metabolic plasticity and metabolic flexibility, contribute to metastasis formation and may be targeted for therapy.

Fig. 2 |. The metabolism of invading and circulating (detached) cancer cells.

Multiple nutrients and metabolites facilitate the invasiveness and migratory abilities of cancer cells (part a) and their survival in the circulation (part b). Differential availability of nutrients and metabolites in the circulation of healthy individuals, patients with non-metastatic cancer (primary tumour) or patients with metastatic cancer have been reported. In the circulation, increased pyruvate levels have been observed in patients with non-metastatic versus metastatic breast cancer (BCa) and for patients with multiple types of cancer compared with healthy individuals. Increased lactate levels have been observed in patients with metastatic colorectal cancer (CRC). Low glutamine and high glutamate levels have been observed in patients with oesophageal squamous cell carcinoma (ESCC). Enhanced lipid levels have been observed in patients with colorectal and breast cancer, but not patients with oral cancer (part c). Fatty acid metabolism is depicted in light indigo. Lactate and pyruvate metabolism are depicted in green. Glutamine metabolism is depicted in dark indigo. Acetate metabolism is depicted in indigo. Asparagine metabolism is depicted in orange. Proteins whose function is regulated by metabolism pathways are shown in light blue. Enzymes depicted in box shape and membrane transporters not coloured in beige have been discussed as targets in the main text. Dashed lines indicate regulatory events. Multiple metabolic reactions are summarized for clarity reasons. Ac, acetylation; ACAT, acetyl-coenzyme A acetyltransferases; ACOT12, acyl-CoA thioesterase 12; ACSS2, acyl-coenzyme A synthetase short-chain family member 2; AMPK, adenosine monophosphate-activated protein kinase; αKG, α-ketoglutarate; ASNS, asparagine synthetase (glutamine-hydrolysing); CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2; c-MYC, MYC proto-oncogene; CoA, coenzyme A; CPT1A, carnitine palmitoyltransferase 1; CTSB, cathepsin B; EMT, epithelial to mesenchymal transition; ER, endoplasmic reticulum; FABP1, fatty acid-binding protein 1; FASN, fatty acid synthase; GDH, glutamate dehydrogenase; GLS1, glutaminase 1; GSH, glutathione; HDAC, histone deacetylases; Her2, Erb-B2 receptor tyrosine kinase 2; HIF2α, hypoxia-inducible factor 2α; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter 1; miR-21, microRNA 21; MMA, methylmalonic acid; MT1-MMP, membrane type 1 matrix metalloproteinase; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κb, nuclear factor κ-light-chain-enhancer of activated B cells; P, phosphorylation; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; Smad2, mothers against decapentaplegic homologue 2; Sox2, SRY (sex determining region Y)-box 2; SPARC, secreted protein acidic and cysteine rich; TCA, tricarboxylic acid; TWIST2, twist family BHLH transcription factor 2; VEGF, vascular endothelial growth factor; Wnt-3a, wingless-type MMTV integration site family, member 3A; xCT, solute carrier family 7 member 11.

Fig. 3 |. The metabolism of cancer cells colonizing in distant organs.

Different nutrients and metabolic pathways are supporting the nesting of metastasizing cancer cells in the lung (part a), lymph node (part b), peritoneum (part c) and brain (part d). In the lung, breast cancer cells take up extracellular pyruvate via monocarboxylate transporter 2 (MCT2) to generate α-ketoglutarate (αKG) from glutamate to activate the enzyme collagen prolyl-4-hydroxylase (P4HA), which is essential for extracellular matrix deposition and remodelling (part a). Uptake of glutamine via ASCT2 is important for the growth of prostate cancer cells and their metastatic seeding to the lung (part a). Elevated fatty acid metabolism is associated with a higher propensity of several cancer cell types to metastasize. Inhibition of CD36 and fatty acid binding proteins (FABPs), which both import fatty acids into the cell, as well as inhibition of fatty acid synthase (FASN) to block de novo fatty acid synthesis has been shown to restrain lung metastases (part a). In lymph nodes, melanoma and breast cancer cells undergo a metabolic shift towards fatty acid oxidation (FAO). Transcriptional co-activator yes-associated protein (YAP) is selectively activated in lymph node metastatic tumours, leading to the upregulation of genes in the FAO signalling pathway (part b). In the peritoneum, visceral adipocytes promote ovarian cancer progression and metastases in the peritoneal cavity by providing fatty acids and increasing CD36 expression in cancer cells (part c). Salt inducible kinase 2 (SIK2)-mediated ACC and SIK2 phosphorylation and overexpression promote fatty acid oxidation required for effective metastasis formation (part c). In the brain, acetate was discovered as an alternative energy source to glucose for human and mouse brain glioblastoma and lung and breast cancer-derived brain metastases (part d). As the brain exhibits low serine levels, inhibiting serine production by genetic phosphoglycerate dehydrogenase (PHGDH) silencing or PH-755 treatment in mice impairs breast cancer-derived brain metastases. *The metabolism of monounsaturated fatty acids can have a pro-metastatic or anti-metastatic function (part a). Fatty acid metabolism is depicted in light indigo. Lactate and pyruvate metabolism are depicted in green. Glutamine metabolism is depicted in dark indigo. Acetate metabolism is depicted in indigo. Serine metabolism is depicted in light orange. Proteins whose function is regulated by metabolism pathways are shown in light blue. Enzymes depicted in box shape and membrane transporters have been discussed as targets in the main text. Dashed lines indicate regulatory events. Multiple metabolic reactions are summarized for clarity reasons. ACC1, acetyl-CoA carboxylase 1; ALT2, alanine aminotransferase 2; CoA, coenzyme A; CPT1/2, carnitine palmitoyltransferase 1/2; ECM, extracellular matrix; ETC, electron transport chain; lncR LNMICC, link RNA LNMICC; P5C, 1-pyrroline-5-carboxylic acid; P, phosphorylation; PC, pyruvate carboxylase; PRODH, proline dehydrogenase; PYCR1, pyrroline-5-carboxylate reductase 1, mitochondrial; SCD1, stearoyl-CoA desaturase 1; SHMT2, serine hydroxymethyltransferase 2; TCA, tricarboxylic acid; xCT, solute carrier family 7 member 11.

Fig. 4 |. Nutrient inflexibility during metastasis formation.

a | Cancer cells can use multiple nutrients to support the specific metabolic needs that arise when transitioning through the metastatic cascade. One example are circulating tumour cells that rely, for example, on lactate, glutamine, oleic acid and cystine to avoid reactive oxygen species (ROS)-induced cell death. Another example are colonizing cancer cells that rely, for example, on fatty acids, proline and glucose to generate sufficient ATP. b | Despite the fact that cancer cells can use multiple nutrients for this purpose, a therapeutically relevant nutrient inflexibility arises. For example, inhibition of lactate or proline uptake is sufficient to impair circulating and colonizing cancer cells, respectively by either inducing cell death or preventing cell division. Consequently, metastasis formation is reduced and may be prevented. Dashed lines in (b) indicate a decrease relative to (a).

Fig. 5 |. Selection and adaptation processes contributing to the metabolic differences between primary tumours and metastases.

Cancer cells growing as a secondary tumour are challenged with a different environment. Either (epi) genetic or metabolic subpopulations of cancer cells from the primary tumour have a selective growth advantage in the new soil, or cancer cells may have the ability to adapt to the new soil. In the case of adaptation, the metabolic make-up of secondary tumours depends on the organ of metastasis rather than the cancer cell origin. In the case of (epi)genetic selection, a subpopulation of cancer cells selected by their (epi)genetic features grows in the secondary site, resulting in a different metabolism depending on the cancer origin. In the case of metabolic selection, a subpopulation of cancer cells selected by their metabolic features grows in the secondary site, resulting in the same metabolism regardless of the cancer origin. It is conceivable that likely a combination of these processes may occur in vivo.