Methionine metabolism in health and cancer: a nexus of diet and precision medicine.

Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.

Dietary methionine influences therapy in mouse cancer models and alters human metabolism.

Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.

Nutrient availability shapes methionine metabolism in p16/MTAP-deleted cells.

Codeletions of gene loci containing tumor suppressors and neighboring metabolic enzymes present an attractive synthetic dependency in cancers. However, the impact that these genetic events have on metabolic processes, which are also dependent on nutrient availability and other environmental factors, is unknown. As a proof of concept, we considered panels of cancer cells with homozygous codeletions in CDKN2a and MTAP, genes respectively encoding the commonly-deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while a metabolic signature of MTAP deletion is apparent, it is not preserved upon restriction of nutrients related to methionine metabolism. Furthermore, re-expression of MTAP exerts heterogeneous consequences on metabolism across isogenic cell pairs. Together, this study demonstrates that numerous factors, particularly nutrition, can overwhelm the effects of metabolic gene deletions on metabolism. These findings may also have relevance to drug development efforts aiming to target methionine metabolism.

Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism.

Mitochondrial metabolism is an attractive target for cancer therapy1,2. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)1,3. Here we show that BTB and CNC homology1 (BACH1)4, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin5,6, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours7. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.

Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer.

BACKGROUND: While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. Furthermore, the effect of exercise on intratumoral metabolic processes has not been investigated in detail in human cancers. In our current study, we generated six colorectal patient patient-derived xenografts (CRC PDXs) models and treated each PDX to voluntary wheel running (exercise) for 6-8 weeks or no exposure to the wheel (control). A comprehensive metabolomics analysis was then performed on the PDXs to identify exercise induced changes in the tumor that were associated with slower growth. RESULTS: Tumor growth inhibition was observed in the voluntary wheel running group compared to the control group in three of the six models. A metabolomics analysis first revealed that central carbon metabolism was affected in each model irrespective of treatment. Interestingly, comparison of responsive and resistant models showed that levels of metabolites in nucleotide metabolism, known to be coupled to mitochondrial metabolism, were predictive of response. Furthermore, phosphocreatine levels which are linked to mitochondrial energy demands were associated with inhibition of tumor growth. CONCLUSION: Altogether, this study provides evidence that changes to tumor cell mitochondrial metabolism may underlie in part the benefits of exercise.

Revisiting the Warburg Effect: Some Tumors Hold Their Breath.

Studies have shown that tumors commonly exhibit normal or enhanced respiration in addition to glycolytic metabolism. In this issue, Courtney et al. (2018) report a reduction in mitochondrial function in kidney cancer patients and thus a classic "Warburg Effect" that further illustrates the heterogeneity of human cancer metabolism.

Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism.

Cell proliferation can be dependent on the non-essential amino acid serine, and dietary restriction of serine inhibits tumor growth, but the underlying mechanisms remain incompletely understood. Using a metabolomics approach, we found that serine deprivation most predominantly impacts cellular acylcarnitine levels, a signature of altered mitochondrial function. Fuel utilization from fatty acid, glucose, and glutamine is affected by serine deprivation, as are mitochondrial morphological dynamics leading to increased fragmentation. Interestingly, these changes can occur independently of nucleotide and redox metabolism, two known major functions of serine. A lipidomics analysis revealed an overall decrease in ceramide levels. Importantly, supplementation of the lipid component of bovine serum or C16:0-ceramide could partially restore defects in cell proliferation and mitochondrial fragmentation induced by serine deprivation. Together, these data define a role for serine in supporting mitochondrial function and cell proliferation through ceramide metabolism.

Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development.

Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methylation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced Mat2a expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development.

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.