Cancer metabolic reprogramming and precision medicine-current perspective.

Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1β to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.

Lung cancers are among the most common invasive cancers worldwide and annually lead to high mortality and morbidity. Genomic alterations have been known to control the evolution of hallmarks of cancer in a dynamic way. These molecular alterations combined with epigenomic and post-genomic modifications contribute to formation of these neoplasms. Multiplicity of these changes has made development of personalized therapeutic regimens for these cancers a complex problem. Metabolic reprogramming is one of the main mechanisms in progression of cancers. There have been efforts to model the metabolic reprogramming in cancer using metabolic networks of cancer cells, but there has been no computational framework to model these metabolic transitions in cancer for precision and personalized medicine. We have combined computational, mathematical and experimental methodologies to develop a platform for precision oncology in non-small cell lung cancer (NSCLC) by in silico models of metabolic switches. Our integrative analysis of genomic data from NSCLC has led to discovery of genomic signatures controlling metabolic reprogramming in NSCLC with KRAS mutations. This discovery was proved in vivo and in vitro using drugs blocking different metabolic pathways. We have shown that NSCLC cells and tumors which carry KRAS mutations and have these genomic signatures are addicted to the pentose phosphate pathway (PPP). We have verified and proved the predictive value of these genomic signatures using Patient Derived Xenograft (PDX) tumor models of NSCLC. We are developing a mathematical and computational framework to model these metabolic switches. Our platform is capable of using genomic data from a cell line or tumor to determine the metabolic dependency of them quantitatively and predict the optimized personalized treatments for modulating metabolic pathways aiming to control cancer progression. Citation Format: Iman Tavassoly, Ravi Iyengar. Metabolic reprogramming in non-small cell lung cancer: a precision oncology approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5554. doi:10.1158/1538-7445.AM2017-5554

MicroRNAs (miRNAs) play important role in regulating cellular metabolism, and are currently being explored in cancer. As metabolic reprogramming in cancer is a major mediator of phenotypic plasticity, understanding miRNA-regulated metabolism will provide opportunities to identify miRNA targets that can regulate oncogenic phenotypes by taking control of cellular metabolism. In the present work, we studied the effect of differentially expressed miRNAs on metabolism, and associated oncogenic phenotypes in glioblastoma (GBM) using patient-derived data. Networks of differentially expressed miRNAs and metabolic genes were created and analyzed to identify important miRNAs that regulate major metabolism in GBM. Graph network-based approaches like network diffusion, backbone extraction, and different centrality measures were used to analyze these networks for identification of potential miRNA targets. Important metabolic processes and cellular phenotypes were annotated to trace the functional responses associated with these miRNA-regulated metabolic genes and associated phenotype networks. miRNA-regulated metabolic gene subnetworks of cellular phenotypes were extracted, and important miRNAs regulating these phenotypes were identified. The most important outcome of the study is the target miRNA combinations predicted for five different oncogenic phenotypes that can be tested experimentally for miRNA-based therapeutic design in GBM. Strategies implemented in the study can be used to generate testable hypotheses in other cancer types as well, and design context-specific miRNA-based therapy for individual patient. Their usability can be further extended to other gene regulatory networks in cancer and other genetic diseases.

Lipid metabolic reprogramming is one of the important metabolic characteristics of cancer cells. As major components of lipids, fatty acids provide energy and material basis for cancer cell survival. Abnormal fatty acid metabolism has been found in many cancers. Fatty acid uptake, transport, and synthesis are closely related to the pathogenesis of cancer. Meanwhile, fatty acid changes in the membrane structure of cancer cells and signal transduction mediated by signaling lipids are also helping cancer cells survive in the changing microenvironment. Some of these enzymes and metabolites involved in fatty acid metabolism are emerging as unique cancer biomarkers. Multiple studies have shown that disordered fatty acids can regulate tumor cell proliferation, metastasis, and drug resistance. Therefore, targeting fatty acid metabolism has become a promising treatment strategy. Here, we mainly present metabolic alterations of fatty acids, the basic components of lipids, in cancer. We discuss the cancer treatment based on fatty acid and fatty acid metabolism. These may provide a basis for a better understanding of lipid metabolic reprogramming in cancer, and also provide new ideas for cancer biomarker search, drug development, and combination therapy.

*These authors contributed to the devlopment and review of this manuscript but are unable to endorse the request for NIH funding. On Sept. 20, 2011, the American Association for Cancer Research (AACR) released its inaugural AACR Cancer Progress Report to commemorate the

Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability. By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.

Background: Pancreatic cancer is a serious life-threatening disease due to its highly invasive and metastatic potential. Hyperglycemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). In this study, we elucidate the biological and clinical impact of hyperglycemia in PDAC progression. Methods: Biological impact of hyperglycemia on malignant behavior in PDAC was examined by in vitro and in vivoexperiment. Results: Hyperglycemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycemia enhanced chemoresistance by upregulating ABCB1 expression, and triggered PDAC switch into pure-basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterized by abundant stroma that harbors tumor-promoting properties and chemoresistance. Hyperglycemia promotes production of collagen fiber-related proteins (fibronectin, fibroblast activation protein, COL1A1, and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance, and a favorable tumor microenvironment even under hyperglycemic conditions in vitro and in vivo. Indeed, YAP/TAZ overexpression was significantly associated with worse prognostic outcomes in human PDAC patients. Conclusion: Hyperglycemia induce metabolic reprogramming into a glycolytic phenotype and promote EMT via the YAP/TAZ-Hedgehog signaling axis in PDAC. Hyperglycemia as an initial symptom may be the cause of highly invasive and metastatic potential by inducing YAP/TAZ overexpression, while YAP/TAZ could be a novel therapeutic target in PDAC patients. Citation Format: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba. Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3709.

Metabolic reprogramming in cancer necessitates increased amino acid uptake, which is accomplished by up-regulation of specific amino acid transporters. However, not all tumors rely on any single amino acid transporter for this purpose. Here, we report on the differential up-regulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The up-regulation is evident in TNBC tumors, conventional and patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous TNBC mammary tumor. The up-regulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since cell-surface Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to the induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger. Down-regulation of SLC38A5 in TNBC cells attenuates serine-induced macropinocytosis and reduces cell proliferation significantly as assessed by multiple methods, but does not induce cell death. The Cancer Genome Atlas database corroborates SLC38A5 up-regulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition and proliferation.

Metabolic Reprograming in Cancer.

Nuclear factor erythroid 2-related factor 2 (NRF2) has emerged as a master regulator of cellular redox homeostasis and metabolic reprogramming in cancer. While traditionally known for its role in antioxidant defense, recent evidence highlights NRF2's pivotal involvement in oncogenic metabolism, therapy resistance, and cell fate decisions. In cancer cells, persistent NRF2 activation upregulates cytoprotective genes, promoting proliferation by suppressing apoptosis and enhancing survival under stress conditions. The interplay between oxidative stress, detoxification pathways, and adaptive cellular responses forms a critical foundation for both tumor initiation and progression. Aberrant activation of these mechanisms contributes to genomic instability, increasing DNA mutation rates and cancer susceptibility. This review provides an integrated perspective on the canonical and non-canonical pathways governing NRF2 activation, with a focus on its intricate crosstalk with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We propose a novel dual-axis model that stratifies NRF2 function based on tumor stage and redox status, capturing its context-dependent roles in tumorigenesis. Additionally, we explore the complementary role of NRF1, an ER-resident transcription factor that cooperates with NRF2 to maintain proteostasis and mediate stress resilience. Finally, we examine the therapeutic landscape of NRF2-targeted agents including ML385, PRL295, Omaveloxolone, and DHTI, highlighting their potential for therapeutic use tailored to tumor stage and cellular context.

Metabolic reprogramming in cancer

Simple SummaryHepatocellular carcinoma (HCC) represents an important health problem. At the moment, systemic therapies offered only modest clinical benefits. Thus, HCC represents a cancer extremely difficult to treat, and therapeutic breakthroughs are urgently needed. Metabolic reprogramming of neoplastic cells has been recognized as one of the core hallmarks of cancer. Experimental animal models represent an important tool that allows to investigate metabolic changes underlying HCC development and progression. In the present review, we characterize available rodent models of hepatocarcinogenesis. Moreover, we discuss the possibility that pharmacological targeting of Warburg metabolism may represent an additional tool to improve already available therapeutic approaches for HCC.Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.

Uncontrolled cell proliferation, escape from immune surveillance, and apoptosis are hallmarks of cancer. Cancer cells resort to a number of avenues to acquire and sustain these characteristics. Ability to harness nutrients to supply energy and building blocks for daughter cells through metabolic reprogramming are at the heart of proliferation and neoplastic transformation. This chapter will discuss the nature of metabolic reprogramming and their consequences on tumorigenesis. It will also discuss the role of metabolic reprogramming beyond proliferation such as in controlling redox balance and fighting oxidative stress. It will go on to describe how niche metabolic rewiring helps a sub-population of cancer cells to maintain stemness amid nutrient scarcity, which contributes to therapeutic resistance and relapse.

Tumor microenvironmental nutrients, cellular responses, and cancer

Simple SummaryTumors are a complex ecosystem including not only cancer cells, but also many distinct cell types of the tumor micro-environment. While the Warburg effect assessing high glucose uptake in tumors was recognized a long time ago, metabolic heterogeneity within tumors has only recently been demonstrated. Indeed, several recent studies have highlighted other sources of carbon than glucose, including amino acids, fatty acids and lactate. These newly identified metabolic trajectories modulate key cancer cell features, such as invasion capacities. In addition, cancer metabolic heterogeneity is not restricted to cancer cells. Here, we also describe heterogeneity of Cancer-Associated Fibroblast (CAF) subpopulations and their complex metabolic crosstalk with cancer cells.During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.