Seminars in Cell & Developmental Biology 43 (2015) 1–2

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Editorial

Cancer and metabolism: Why should we care?

This special issue of Seminars in Cell and Developmental Biology covers a wide range of topics associating cancer and cell metabolism. It is difficult to pinpoint exactly when was it that metabolic studies took center stage in the cancer research field. Was it as early as the 1920s, with Otto Warburg’s first proposals, which have been highly debated ever since [1]? Was it with the introduction of anti-folate chemotherapy by Sydney Farber in the 1940s [2]? Was it with the first attempts to treat patients with 2-deoxyglucose in the 1950s [3] or with the first use of 18 fluoro-deoxyglucose for cancer imaging in the 1980 [4]? Perhaps it was with the discovery of oxygen sensitive transcription factors (hypoxia inducible factor – HIFs) [5] or of the nutrient-dependent kinase (mammalian/mechanistic target of rapamycin – mTOR) [6,7] in the 1990? Or did the numerous discoveries linking metabolism to epigenetics [8,9] and metabolic genes with tumor suppression or oncogenesis [10] clinch the status of metabolism in the field? Every individual who works on cancer metabolism in one way or another has their own ‘entry point’. However, one thing is clear: young medical or research students stepping into the worlds of oncology or cancer research, can no longer take basic biochemical courses lightly. A new chapter was added to the history of cancer metabolism during the past decade, with the incorporation of ‘metabolomics’ into cancer research. Here, the traditional link between cancer biology and medicinal chemistry was expanded and intensified by bringing in analytical chemistry. Engineers and mathematicians further advanced the field by adapting new technologies including isotope tracing, fluxomics and computational metabolic models. The field has become an intellectual ‘tour de force’ that invigorates the imagination of many of us, and has by now led to countless new discoveries, many of which are summarized in this collection of reviews. But perhaps even more importantly, it has opened the eyes and doors of both established and new bio-industries to the potential of translating this sea of knowledge into the future of clinical management. In this Special Issue, we try to convey the knowledge we have acquired in this past decade, putting in perspective the different players that make the field of cancer metabolism the vast discipline that it is today. In this context, it has become clear that multiple proteins have evolved as potent oncogenes through their ability to provide metabolic adaptations that are key for cancer cells to survive and proliferate. Celeste Simon and Bo Qiu nicely summarize our current knowledge on these factors and their roles in adaptive metabolism of cancer cells. In particular, the transcription factor http://dx.doi.org/10.1016/j.semcdb.2015.10.007 1084-9521/© 2015 Published by Elsevier Ltd.

Myc represents the ultimate example of a multifunctional protein that has evolved as an oncogene “par excellence”, and Chi Dang and colleagues provide in their chapter a comprehensive account of Myc roles in coordinating the different carbon sources with protein, lipid and nucleotide synthesis. A key feature of cancer cells is to co-opt nutrient sensing factors to maximize the usage of available resources. mTOR, exemplifies one of the most important nutrient sensors. Richard Possemato and Zhi-Yang Tsun focus their Chapter on the key roles of mTOR in sensing and managing amino acids in cancer cells. Other important metabolic adaptors are the sirtuins, a family of NAD-dependent protein deacylases with multiple roles in metabolism, DNA repair and aging. Not surprising, several sirtuins have been described with tumor-suppressor and oncogenic features. Raul Mostoslavsky and Carlos Sebastian provide an update on this unique group of enzymes. Few metabolic enzymes are recognized as key limiting factors in modulating intermediate metabolism, and among them, the pyruvate kinase isoform PKM2 appears to specifically have evolved to drive metabolic adaptations in tumor cells. Matt Vander-Heiden and William Israelsen deliver in their Chapter a detailed account of this unique enzyme’s biochemical, enzymatic and cellular functions. Lastly, the vast new knowledge we have accumulated in the past few years provide us with unique opportunities to exploit metabolic liabilities of cancer cells for novel therapies. Eyal Gottlieb and colleagues summarize in their Chapter where we stand and where we are heading in the context of clinical management and targeting metabolism in oncology. There is still no guaranty that the field of cancer metabolism, in its ‘modern’ form, will indeed deliver new medicines or diagnostic and prognostic tools. But even so, a prolific scientific discipline, aiming at discovery per se must not depend on nor be evaluated according to its translational merit only. However, we all share high hopes that research into cancer metabolism and metabolomics will match and even surpass past and ongoing clinical achievements in the branches of cell signaling and genomics. References [1] Warburg O. On the origin of cancer cells. Science 1956;123:309–14. [2] Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med 1948;238:787–93. [3] Landau BR, Laszlo J, Stengle J, Burk D. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-d-glucose. J. Natl. Cancer Inst 1958;21:485–94.

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Editorial / Seminars in Cell & Developmental Biology 43 (2015) 1–2

[4] Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, et al. A fluorinated glucose analog, 2-fluoro-2-deoxy-d-glucose (F-18): nontoxic tracer for rapid tumor detection. J. Nucl. Med 1980;21: 670–5. [5] Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem 1995;270:1230–7. [6] Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756–8. [7] Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35–43. [8] Nowicki S, Gottlieb E. Oncometabolites: tailoring our genes. FEBS J 2015. [9] Martinez-Pastor B, Cosentino C, Mostoslavsky R. A tale of metabolites: the cross-talk between chromatin and energy metabolism. Cancer Discov 2013;3:497–501. [10] Frezza C, Pollard PJ, Gottlieb E. Inborn and acquired metabolic defects in cancer. J. Mol. Med. (Berl.) 2011;89:213–20.

Eyal Gottlieb ∗ Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, United Kingdom Raul Mostoslavsky ∗ The Massachusetts General Hospital Cancer Center-Harvard Medical School, Boston, MA 02114, USA ∗ Corresponding authors. E-mail addresses: [email protected] (E. Gottlieb), [email protected] (R. Mostoslavsky).

Cancer and metabolism: Why should we care?

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