Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment
Authors: Barrie Peck, Almut Schulze
Journal: Trends in cancer (2019)

Obesity and excess caloric intake promotes cancer aggressiveness, reduces response to chemotherapy and increases the likelihood of reoccurrence, yet little is known about how to better target tumors in these patients.Altered metabolism is a common feature of human cancers. Distinct metabolic phenotypes are often caused by a combination of tissue specific contexts and distinct genomic alterations of the tumor.Lipid metabolism represents a therapeutic opportunity in many tumor types. To translate these therapies into the clinic it is necessary to establish robust genomic, histological and biometric biomarkers for modulators of lipid metabolism.Utilizing diet as a modality to increase therapy efficacy could have significant effect in some tumors. Obesity is a leading contributing factor to cancer development worldwide. Epidemiological evidence suggests that diet affects cancer risk and also substantially alters therapeutic outcome. Therefore, studying the impact of diet in the development and treatment of cancer should be a clinical priority. In this Review, we set out the evidence supporting the role of lipid metabolism in shaping the tumor microenvironment (TME) and cancer cell phenotype. We will discuss how dietary lipids can impact phenotype thereby affecting disease trajectory and treatment response. Finally, we will posit potential strategies on how this knowledge can be exploited to increase treatment efficacy and patient survival. Obesity is a leading contributing factor to cancer development worldwide. Epidemiological evidence suggests that diet affects cancer risk and also substantially alters therapeutic outcome. Therefore, studying the impact of diet in the development and treatment of cancer should be a clinical priority. In this Review, we set out the evidence supporting the role of lipid metabolism in shaping the tumor microenvironment (TME) and cancer cell phenotype. We will discuss how dietary lipids can impact phenotype thereby affecting disease trajectory and treatment response. Finally, we will posit potential strategies on how this knowledge can be exploited to increase treatment efficacy and patient survival. Excess caloric intake leads to obesity and is a major risk factor for diabetes, cardiovascular disease, stroke, and incidence of cancer worldwide. Indeed, high body fat is associated with an increased likelihood of developing multiple hematological malignancies, and breast, esophageal, renal, colon, pancreatic, and endometrial cancers [1Renehan A.G. et al.Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3279) Google Scholar]. Prospective analysis of 900 000 cancer-free adults in the US showed that men and women with the highest body mass index (BMI) had a 52% and 62% increased risk, respectively, of dying from cancer than their normal weight counterparts [2Calle E.E. et al.Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N. Engl. J. Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5461) Google Scholar]. Increased body weight and fat tissue results in altered hormone levels, such as increased estrogen and insulin, which play major roles in cancer development and can result in systemic metabolic changes; that is, hyperglycemia (see Glossary; due to insulin resistance) or elevated levels of circulating lipids. Obesity also promotes tissue inflammation and vascular dysfunction [3Font-Burgada J. et al.Obesity and cancer: the oil that feeds the flame.Cell Metab. 2016; 23: 48-62Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. However, there is limited understanding of the direct impact that diet has on cells within the TME. For example, it is not well known if elevated blood glucose levels promote the proliferation of cancer cells or if increased lipid availability in the TME promotes cancer cells to use these lipids as an energy source or substrates for membrane synthesis. Epidemiological evidence suggests that diet substantially alters treatment outcome in cancer patients; that is, meta-analyses show that breast cancer recurrence is 30% higher in obese women compared to their normal-weight counterparts [4Goodwin P.J. Obesity and Breast cancer outcomes: how much evidence is needed to change practice?.J. Clin. Oncol. 2016; 34: 646-648Crossref PubMed Scopus (20) Google Scholar]. Therefore, a better understanding of the effect of diet, in particular the carbohydrate- and fat-rich western diet, on nutrient availability within the TME and its impact on signaling pathways that determine drug sensitivity is essential for the development of novel anticancer therapies. In this Review, we discuss lipid metabolism within the context of the TME and explore how diet can impact cancer phenotype, disease trajectory, and treatment response. The synthesis of lipids is a highly coordinated and controlled molecular program regulated by the sterol regulatory element binding proteins (SREBPs), which respond to upstream signaling networks (i.e., PI3K/AKT/mTORC1 pathway) and to the cellular nutrient status (i.e., environment deplete of lipids [5Nohturfft A. Zhang S.C. Coordination of lipid metabolism in membrane biogenesis.Annu. Rev. Cell Dev. 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Indeed, ccRCCs are histologically defined by the presence of large organelles that store glycogen and lipids, thus altered lipid metabolism is central to the tumor phenotype [11Gebhard R.L. et al.Abnormal cholesterol metabolism in renal clear cell carcinoma.J. Lipid Res. 1987; 28: 1177-1184Abstract Full Text PDF PubMed Google Scholar]. Cancer mutations converge on deregulated metabolism [12Gatto F. et al.Systematic analysis reveals that cancer mutations converge on deregulated metabolism of arachidonate and xenobiotics.Cell Rep. 2016; 16: 878-895Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] and oncogenic hotspot mutations are also found in metabolic enzymes. For instance, mutations in IDH occur in low-grade gliomas, secondary glioblastomas, and acute myelogenous leukemias (AML) [13Yan H. et al.IDH1 and IDH2 mutations in gliomas.N. Engl. J. 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Wild-type isocitrate dehydrogenase (IDH) proteins in cancer can also reductively carboxylate α-ketoglutarate to generate citrate, allowing glutamine-derived carbon atoms to be shuttled into lipid synthesis, particularly when the activity of the tricarboxylic acid (TCA) cycle is impaired, such as under hypoxic conditions or in cells with defective mitochondria [10Metallo C.M. et al.Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.Nature. 2012; 481: 380-384Crossref Scopus (1013) Google Scholar, 16Wise D.R. et al.Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability.Proc. Natl. Acad. Sci. U S A. 2011; 108: 19611-19616Crossref PubMed Scopus (614) Google Scholar, 17Mullen A.R. et al.Reductive carboxylation supports growth in tumour cells with defective mitochondria.Nature. 2011; 481: 385-388Crossref PubMed Scopus (746) Google Scholar]. IDH1 protein expression is also upregulated in primary glioblastomas, with its inhibition resulting in decreased levels of α-ketoglutarate, reduced NADPH production, and lower flux of acetate- and glucose-derived carbon into lipids [18Calvert A.E. et al.Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation.Cell Rep. 2017; 19: 1858-1873Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. These metabolic changes are accompanied by altered histone methylation and differential expression of differentiation markers [15Turcan S. et al.IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.Nature. 2012; 483: 479-483Crossref PubMed Scopus (1227) Google Scholar, 18Calvert A.E. et al.Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation.Cell Rep. 2017; 19: 1858-1873Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar], suggesting that alterations in metabolic genes not only impact metabolic pathways but can also affect global gene expression through epigenetic mechanisms. Specific components of the lipogenic machinery have been shown to play a protumorigenic role in several cancers. For example, fatty acid synthase (FASN), a key downstream target of SREBP responsible for the NADPH-dependent synthesis of palmitate (Figure 1), is upregulated in breast, prostate, ovarian, stomach, and colorectal cancers [19Menendez J.A. Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.Nat. Rev. Cancer. 2007; 7: 763-777Crossref PubMed Scopus (1718) Google Scholar]. Increased FASN expression correlates with established oncogenic events, such as HER2 amplification in breast cancer [20Kumar-Sinha C. et al.Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis.Cancer Res. 2003; 63: 132-139PubMed Google Scholar] and PTEN loss in prostate and ovarian cancers [21Bandyopadhyay S. et al.FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis.Oncogene. 2005; 24: 5389-5395Crossref PubMed Scopus (98) Google Scholar, 22Wang H.Q. et al.Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells.Oncogene. 2005; 24: 3574-3582Crossref PubMed Scopus (155) Google Scholar]. Efforts to efficiently block FASN for cancer treatment have been hampered by unexpected toxicity and metabolic compensation via lipid uptake [6Rohrig F. Schulze A. The multifaceted roles of fatty acid synthesis in cancer.Nat. Rev. Cancer. 2016; 16: 732-749Crossref PubMed Scopus (424) Google Scholar]. Thus, lipid metabolism is indispensable for tumor progression and targeting it can be efficacious in cancer, but understanding the conditions and context that imparts sensitivity to inhibition is key to the development of successful treatment strategies. Genetic intratumor heterogeneity is central to tumor evolution and drug resistance [23McGranahan N. Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future.Cell. 2017; 168: 613-628Abstract Full Text Full Text PDF PubMed Scopus (910) Google Scholar]. However, it is also clear that solid tumors must contain substantial metabolic intratumor heterogeneity, in part as a result of gradients of blood-derived nutrients and oxygen delivered by the tumor vasculature into the TME. Oxygen availability impacts cancer cells, as low oxygen (hypoxia) results in the stabilization and activation of HIF proteins that drive the transcription of distinct sets of target genes allowing metabolic adaptation. The presence of tumor hypoxia by the histological detection of HIFs, or their downstream targets, is associated with a poor clinical outcome in cancer patients, particularly in invasive tumors of a higher grade or more aggressive stage [24Trastour C. et al.HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome.Int. J. Cancer. 2007; 120: 1451-1458Crossref PubMed Scopus (182) Google Scholar, 25Vleugel M.M. et al.Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer.J. Clin. 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Thus, local TME nutrient levels have a substantial impact on tumor phenotype, particularly in individuals whose circulating nutrient levels are consistently in excess and whose tumors have a genomic architecture that imparts an auxotrophic phenotype for specific factors; such as, KRASv12-driven tumors dependent on macropinocytosis to scavenge nutrients from their local microenvironment [32Finicle B.T. et al.Nutrient scavenging in cancer.Nat. Rev. Cancer. 2018; 18: 619-633Crossref PubMed Scopus (73) Google Scholar]. The cellular response to lipid and oxygen depletion is not necessarily distinct. Indeed, SREBPs are part of an oxygen-sensing pathway in yeast controlling the expression of hypoxia-dependent genes [33Lee C.Y. et al.Oxygen-dependent binding of Nro1 to the prolyl hydroxylase Ofd1 regulates SREBP degradation in yeast.EMBO J. 2009; 28: 135-143Crossref PubMed Scopus (34) Google Scholar]. 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Desaturation is indispensable in cancer to avoid lipotoxicity under conditions of nutrient stress, be it through dependency on steroyl-CoA desaturase (SCD) or fatty acid desaturase 2 (FADS2) [37Peck B. et al.Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments.Cancer Metab. 2016; 4: 6Crossref PubMed Google Scholar, 38Vriens K. et al.Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.Nature. 2019; 566: 403-406Crossref PubMed Scopus (117) Google Scholar]. Maintenance of lipid synthesis under hypoxic conditions promotes cancer cell survival but the contribution of glucose-derived carbon to generate citrate and acetyl-CoA via the TCA cycle is compromised, due to the shunting of pyruvate to lactate. Under hypoxia, cancer cells shift the production of acetyl-CoA from glucose to glutamine as maintenance of lipid synthesis is essential for cell survival [16Wise D.R. et al.Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability.Proc. Natl. Acad. Sci. U S A. 2011; 108: 19611-19616Crossref PubMed Scopus (614) Google Scholar, 17Mullen A.R. et al.Reductive carboxylation supports growth in tumour cells with defective mitochondria.Nature. 2011; 481: 385-388Crossref PubMed Scopus (746) Google Scholar]. Indeed, HIF1 activation promotes SIAH2-mediated degradation of OGDN2, resulting in a shunt of glutamine-derived carbon into FA synthesis [39Sun R.C. Denko N.C. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth.Cell Metab. 2014; 19: 285-292Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar]. More recently we and others identified acetyl-CoA synthetase 2 (ACSS2) to be a novel drug target in aggressive breast, brain, prostate, ovary and lung cancers [40Schug Z.T. et al.Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress.Cancer Cell. 2015; 27: 57-71Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 41Comerford S.A. et al.Acetate dependence of tumors.Cell. 2014; 159: 1591-1602Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 42Mashimo T. et al.Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.Cell. 2014; 159: 1603-1614Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 43Kamphorst J.J. et al.Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate.Cancer Metab. 2014; 2: 23Crossref PubMed Google Scholar]. ACSS2 expression is driven by SREBP2 under metabolic stress [40Schug Z.T. et al.Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress.Cancer Cell. 2015; 27: 57-71Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar] and extracellular acidification [44Kondo A. et al.Extracellular acidic pH activates the sterol regulatory element-binding protein 2 to promote tumor progression.Cell Rep. 2017; 18: 2228-2242Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar] allowing for the conversion of acetate to acetyl-CoA for lipid synthesis. Lipid metabolism is also important in disease recurrence and metastasis formation. Two distinct murine models of breast cancer (MYC/KRAS and MYC/NEU) showed an upregulation of genes involved in FA metabolism in tumors treated with neoadjuvant therapy, suggesting it is a common feature of residual disease [45Havas K.M. et al.Metabolic shifts in residual breast cancer drive tumor recurrence.J. Clin. Invest. 2017; 127: 2091-2105Crossref PubMed Scopus (54) Google Scholar]. In ovarian cancer, the primary metastatic site is the adipocyte-rich omentum and adipocytes secrete adipokines coercing cancer cells to selectively metastasize to this tissue. It has been shown that ommental adipocytes release free FAs that are taken up by ovarian cancer cells in a fatty acid binding protein 4 (FABP4)-dependent manner for FAO and energy generation [46Nieman K.M. et al.Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1128) Google Scholar]. While enhanced lipid synthesis supports cell growth and proliferation, cancer cells also have to protect their lipid pools from oxidative damage. In ccRCC cells inhibition of glutathione peroxidase 4 (GPX4), which removes lipid peroxides from membrane lipids, results in the induction of ferroptosis [47Miess H. et al.The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma.Oncogene. 2018; 37: 5435-5450Crossref PubMed Scopus (65) Google Scholar, 48Zou Y. et al.A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.Nat. Commun. 2019; 10: 1617Crossref PubMed Scopus (115) Google Scholar]. 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As mentioned previously, SREBPs also control serum-derived lipid uptake through regulating the expression of the low-density lipoprotein receptor (LDLR). In pancreatic cancers and glioblastomas, SREBPs upregulate LDLR expression, resulting in the enhanced uptake and storage of cholesteryl esters (CEs) in lipid droplets in an acetyl-coenzyme acetyltransferase 1 (ACAT1/SOAT1)-dependent manner. This results in a positive feedback loop that maintains high PI3K/AKT/mTOR/SREBP activity and fuels cancer aggressiveness [51Yue S. et al.Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.Cell Metab. 2014; 19: 393-406Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, 52Li J. et al.Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer.Oncogene. 2016; 35: 6378-6388Crossref PubMed Scopus (98) Google Scholar]. It is likely that cancer cells attempt to fulfill their lipid demand through lipid uptake as long as lipids are readily available within the TME. Ras-driven tumors, such as lung adenocarcinomas (LUACs) and pancreatic ductal adenocarcinomas (PDACs), harbor recurrent activating hotspot mutations in the oncogene K-ras. Ras-transformed cells exhibit an endocytic phenotype in which they take up and catabolize extracellular proteins to fuel cellular bioenergetics and growth [32Finicle B.T. et al.Nutrient scavenging in cancer.Nat. Rev. Cancer. 2018; 18: 619-633Crossref PubMed Scopus (73) Google Scholar]. This hard-wired dependency results in enhanced sensitivity towards macropinocytosis inhibitors in K-ras-mutant but not wild-type PDAC xenografts [53Commisso C. et al.Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.Nature. 2013; 497: 633-637Crossref PubMed Scopus (820) Google Scholar]. In addition, tumor-associated stromal cells present in the TME can be coerced into supporting specific metabolic phenotypes to aid cancer growth. For example, pancreatic stellate cells (PSCs) undergo transdifferentiation into cancer-associated fibroblasts (CAFs), resulting in metabolic rewiring and excretion of lysophosphatidylcholine into the TME, which is then metabolized to lysophosphatidic acid (LPA) by autotaxin [54Auciello F.R. et al.A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression.Cancer Discov. 2019; 9: 617-627Crossref PubMed Scopus (65) Google Scholar]. As LPA is an important lipid mediator, this stromal signaling axis promotes tumor growth and disease progression [54Auciello F.R. et al.A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression.Cancer Discov. 2019; 9: 617-627Crossref PubMed Scopus (65) Google Scholar]. While multiple preclinical studies have clearly demonstrated the importance of lipid provision for cancer growth, they are mostly performed under standard conditions where the nutritional aspects of a western diet are not included. It is likely that the metabolic composition of the TME, and heterotypic cellular relationship of cancer and non-cancer cells within it, will be distinct in cancers arising in individuals exposed to different diets and nutritional regimens, such as those consuming a high-fat diet (HFD). The impact of different diets on RAS-dependent cancer initiation and development was studied in a mouse model of sporadic cancer. Mice were generated with inducible RasV12 expression that produced a mosaic of transformed epithelial cells in the pancreas and small intestine [55Sasaki A. et al.Obesity suppresses cell-competition-mediated apical elimination of RasV12-transformed cells from epithelial tissues.Cell Rep. 2018; 23: 974-982Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Mice previously fed a HFD displayed reduced extrusion of transformed cells from the mosaic tissues, suggesting exogenous lipid supply aided the persistence of transformed cells promoting tissue dysplasia [55Sasaki A. et al.Obesity suppresses cell-competition-mediated apical elimination of RasV12-transformed cells from epithelial tissues.Cell Rep. 2018; 23: 974-982Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. This could be phenocopied in vitro, where addition of FAs, particularly palmitate, reduced apical extrusion of epithelial cells from the monolayer in a dose-dependent manner [55Sasaki A. et al.Obesity suppresses cell-competition-mediated apical elimination of RasV12-transformed cells from epithelial tissues.Cell Rep. 2018; 23: 974-982Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Moreover, in several mutant KRas preclinical PDAC models, tumor growth and metastasis were increased in mice fed a HFD [56Incio J. et al.Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy.Cancer Discov. 2016; 6: 852-869Crossref PubMed Scopus (161) Google Scholar, 57Incio J. et al.PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity.Clin. Cancer Res. 2016; 22: 2993-30