Cancer metabolism: Addicted to serine.

Cancer cells are biosynthetic factories that gear multiple metabolic pathways toward cell growth and proliferation. Serine is the metabolite consumed third most by cancer cells, after glucose and glutamine, and is used as a building block for proteins and as a carbon donor for nucleotide biosynthesis. Serine can also be synthesized de novo from glucose (Fig. 1, left). Studies in the late 1980s demonstrated that de novo synthesis of serine is increased in cancer cells, suggesting that this pathway might be relevant for their growth. But it was not until the landmark discovery thatphosphoglycerate dehydrogenase (encoded by PHGDH), the first step of de novo serine synthesis, is genomically amplified in breast cancer and melanoma that this pathway came into the limelight. Importantly, silencing PHGDH in PHGDH-dependent cancers significantly affects their growth, making this enzyme an excellent target for cancer therapy. Recent work from Mullarky et al. reported the discovery of a novel noncompetitive inhibitor of PHGDH. However, although this compound was selective against PHGDH-dependent melanoma and breast cancer cell lines, it was unstable in mouse plasma, limiting its use in vivo. In this issue of Nature Chemical Biology, Pacold et al. report the discovery of small-molecule inhibitors of PHGDH that exhibit potent antitumor activity both in vitro an in vivo.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nchembio.208

Oncometabolites: Unconventional triggers of oncogenic signalling cascades.

Cancer is a complex and heterogeneous disease thought to be caused by multiple genetic lesions. The recent finding that enzymes of the tricarboxylic acid (TCA) cycle are mutated in cancer rekindled the hypothesis that altered metabolism might also have a role in cellular transformation. Attempts to link mitochondrial dysfunction to cancer uncovered the unexpected role of small molecule metabolites, now known as oncometabolites, in tumorigenesis. In this review, we describe how oncometabolites can contribute to tumorigenesis. We propose that lesions of oncogenes and tumour suppressors are only one of the possible routes to tumorigenesis, which include accumulation of oncometabolites triggered by environmental cues.MS and CF are funded by an MRC Core Funding to the MRC Cancer Unit.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.02

IL-10-Mediated Refueling of Exhausted T Cell Mitochondria Boosts Anti-Tumour Immunity.

Immunotherapy has underscored a revolution in cancer treatment. Yet, many patients fail to respond due to T cell exhaustion. Here, an intervention that restores mitochondrial function reversed the exhausted T cell phenotype to promote cytotoxicity and durable anti-tumour responses in vivo

Editorial: The Metabolic Challenges of Immune Cells in Health and Disease.

Copyright: © 2015 Frezza and Mauro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.CM is supported by the British Heart Foundation Fellowship FS/12/38/29640. CF is funded by the UK Medical Research Council

Mitochondrial DNA: the overlooked oncogenome?

Perturbed mitochondrial bioenergetics constitute a core pillar of cancer-associated metabolic dysfunction. While mitochondrial dysfunction in cancer may result from myriad biochemical causes, a historically neglected source is that of the mitochondrial genome. Recent large-scale sequencing efforts and clinical studies have highlighted the prevalence of mutations in mitochondrial DNA (mtDNA) in human tumours and their potential roles in cancer progression. In this review we discuss the biology of the mitochondrial genome, sources of mtDNA mutations, and experimental evidence of a role for mtDNA mutations in cancer. We also propose a 'metabolic licensing' model for mtDNA mutation-derived dysfunction in cancer initiation and progression

Immunohistochemistry as a tool for screening rare renal cancers

Recent additions of succinate dehydrogenase (SDH) and (Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC, associated) fumarate hydratase (FH)-deficient renal cell carcinomas (RCC) to the 2016 WHO Classification of Renal Tumours (1) have highlighted an evolving need for the distinction between renal cancer subtypes. Differences in molecular characterisation, clinical phenotypes, and therapeutic responses (1-3) further corroborates this paradigm shift and strongly points towards the development of subtype-specific management (3). SDH and FH-deficient RCCs are rare tumours strongly associated with hereditary neoplastic syndromes and early-onset(2, 4, 5). FH-deficient RCCs are highly aggressive tumours associated with poor patient prognosis(2, 3, 6), whereas SDH-deficient RCCs are phenotypically more variable, but alsoThis work was supported by the Wellcome Trust (to C Yong), The Urology Foundation (to C Yong), and by the Medical Research Council (to C Frezza) (MRC_MC_UU_12022/6)

Fumarate hydratase in cancer: A multifaceted tumour suppressor.

Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.MS and CF are funded by an MRC Core Funding to the MRC Cancer Unit MRC_MC_UU_12022/6, CS is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 722605

Metabolism and cancer: the future is now

Abstract: In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled

Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival.

Cancer cells undergo a multifaceted rewiring of cellular metabolism to support their biosynthetic needs. Although the major determinants of this metabolic transformation have been elucidated, their broad biological implications and clinical relevance are unclear. Here we systematically analyse the expression of metabolic genes across 20 different cancer types and investigate their impact on clinical outcome. We find that cancers undergo a tissue-specific metabolic rewiring, which converges towards a common metabolic landscape. Of note, downregulation of mitochondrial genes is associated with the worst clinical outcome across all cancer types and correlates with the expression of epithelial-to-mesenchymal transition gene signature, a feature of invasive and metastatic cancers. Consistently, suppression of mitochondrial genes is identified as a key metabolic signature of metastatic melanoma and renal cancer, and metastatic cell lines. This comprehensive analysis reveals unexpected facets of cancer metabolism, with important implications for cancer patients' stratification, prognosis and therapy.C.F. and E.G. thank Medical Research Council (MRC) Core funding for financial support. E.G. was supported by MRC Doctoral Training Partnership (DTP) studentshi