From modulation of cellular plasticity to potentiation of therapeutic resistance: new and emerging roles of MYB transcription factors in human malignancies.

MYB transcription factors are encoded by a large family of highly conserved genes from plants to vertebrates. There are three members of the MYB gene family in human, namely, MYB, MYBL1, and MYBL2 that encode MYB/c-MYB, MYBL1/A-MYB, and MYBL2/B-MYB, respectively. MYB was the first member to be identified as a cellular homolog of the v-myb oncogene carried by the avian myeloblastosis virus (AMV) causing leukemia in chickens. Under the normal scenario, MYB is predominantly expressed in hematopoietic tissues, colonic crypts, and neural stem cells and plays a role in maintaining the undifferentiated state of the cells. Over the years, aberrant expression of MYB genes has been reported in several malignancies and recent years have witnessed tremendous progress in understanding of their roles in processes associated with cancer development. Here, we review various MYB alterations reported in cancer along with the roles of MYB family proteins in tumor cell plasticity, therapy resistance, and other hallmarks of cancer. We also discuss studies that provide mechanistic insights into the oncogenic functions of MYB transcription factors to identify potential therapeutic vulnerabilities.

Mitochondrial Translocase TOMM22 Is Overexpressed in Pancreatic Cancer and Promotes Aggressive Growth by Modulating Mitochondrial Protein Import and Function.

Pancreatic cancer has the worst prognosis among all cancers, underscoring the need for improved management strategies. Dysregulated mitochondrial function is a common feature in several malignancies, including pancreatic cancer. Although mitochondria have their own genome, most mitochondrial proteins are nuclear-encoded and imported by a multi-subunit translocase of the outer mitochondrial membrane (TOMM). TOMM22 is the central receptor of the TOMM complex and plays a role in complex assembly. Pathobiologic roles of TOMM subunits remain largely unexplored. Here we report that TOMM22 protein/mRNA is overexpressed in pancreatic cancer and inversely correlated with disease outcomes. TOMM22 silencing decreased, while its forced overexpression promoted the growth and malignant potential of the pancreatic cancer cells. Increased import of several mitochondrial proteins, including those associated with mitochondrial respiration, was observed upon TOMM22 overexpression which was associated with increased RCI activity, NAD+/NADH ratio, oxygen consumption rate, membrane potential, and ATP production. Inhibition of RCI activity decreased ATP levels and suppressed pancreatic cancer cell growth and malignant behavior confirming that increased TOMM22 expression mediated the phenotypic changes via its modulation of mitochondrial protein import and functions. Altogether, these results suggest that TOMM22 overexpression plays a significant role in pancreatic cancer pathobiology by altering mitochondrial protein import and functions. IMPLICATIONS: TOMM22 bears potential for early diagnostic/prognostic biomarker development and therapeutic targeting for better management of patients with pancreatic cancer.

MYB exhibits racially disparate expression, clinicopathologic association, and predictive potential for biochemical recurrence in prostate cancer.

MYB acts as a potentiator of aggressiveness and castration resistance in prostate cancer (PCa) through aberrant activation of androgen receptor (AR) signaling. Since Black men experience higher PCa incidence and mortality than White men, we examined if MYB was differentially expressed in prostate tumors from patients of these racial backgrounds. The data reveal that aberrant MYB expression starts early in precancerous high-grade prostate intraepithelial neoplastic lesions and increases progressively in malignant cells. PCa tissues from Black patients exhibit higher MYB expression than White patients in overall and grade-wise comparisons. MYB also exhibits a positive correlation with AR expression and both display higher expression in advanced tumor stages. Notably, we find that MYB is a better predictor of biochemical recurrence than AR, pre-treatment PSA, or Gleason's grades. These findings establish MYB as a promising molecular target in PCa that could be used for improved risk prediction and therapeutic planning.

MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.

Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle-related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma.

There is a complete lack of highly sensitive and specific biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis, limiting multi-modal therapeutic options. Mitochondrial DNA (mtDNA) is an excellent resource for biomarker discovery because of its high copy number and increased mutational frequency in cancer cells. We examined if mtDNA mutations can be detected in circulating extracellular vesicles (EVs) of PDAC patients and used for discerning between cancer and non-cancer subjects. A greater yield of circulating EVs (~ 1.4 fold; p = 0.002) was obtained in PDAC patients (n = 20) than non-cancer (NC) individuals (n = 10). PDAC-EVs contained a higher quantity of total DNA (~ 5.5 folds; p = 0.0001) than NC-EVs and had greater enrichment of mtDNA (~ 14.02-fold; p = 0.0001). PDAC-EVs also had higher levels of cardiolipin (a mitochondrial inner-membrane phospholipid), suggestive of their mitochondrial origin. All mtDNA mutations in PDAC-EVs were unique and frequency was remarkably higher. Most mtDNA mutations (41.5%) in PDAC-EVs were in the respiratory complex-I (RCI) (ND1-ND6), followed by the RCIII gene (CYTB; 11.2%). Among the non-coding genes, D-Loop and RNR2 exhibited the most mutations (15.2% each). Altogether, our study establishes, for the first time, that mtDNA mutations can be detected in circulating EVs and potentially serve as a tool for reliable PDAC diagnosis.

Determining the Size Distribution and Integrity of Extracellular Vesicles by Dynamic Light Scattering.

Extracellular vesicles (EVs) have emerged as significant players in intercellular communication. They carry crucial biological information, and their uptake induces changes in the biological functioning and phenotypes of the recipient cell. Thus, there has been a great deal of interest in understanding their roles in the pathobiology of benign diseases and cancer. Moreover, EVs carry the molecular signatures of the donor cells, and therefore, their utility in biomarker development is being explored. Investigations are also underway to exploit their natural property of cargo transfer from one cell to another to develop efficient, nontoxic, and nonimmunogenic drug delivery systems. EVs originate through endosomal pathways, membrane-budding, or membrane-blebbing during apoptosis. These EV subtypes are usually expected to follow a specific size and surface marker distribution reflective of their origin; however, variations are often reported, especially under pathobiological conditions. Therefore, they are categorized mainly based on their size distribution as small, medium, and large EVs. Dynamic Light Scattering (DLS) is frequently used to measure the size distribution of nanoscale particles in a solution. Moreover, it also provides data on other biophysical properties such as polydispersity, aggregation, solubility, viscosity, and stability. This chapter describes the methods for determining the size distribution and integrity of EVs using DLS along with some constraints associated with the practical use of the technology.

Nicotine causes alternative polarization of macrophages via Src-mediated STAT3 activation: Potential pathobiological implications.

Nicotine is an addictive ingredient of tobacco products and other noncigarette substitutes, including those being used for smoking cessation to relieve withdrawal symptoms. Earlier research, however, has associated nicotine with the risk and poorer outcome of several diseases, including cancer. Macrophages are an important component of the innate immune system and can have both pro-and anti-inflammatory functions depending upon their polarization state. Here, we investigated the effect of nicotine on macrophage polarization, growth, and invasion to understand its role in human physiology. We observed that nicotine induced M2 polarization of RAW264.7 and THP-1-derived macrophages in a dose-dependent manner. Cytokine profiling suggested a mixed M2a/d phenotype of nicotine-polarized macrophages associated with tissue repair and pro-angiogenic functions. Moreover, nicotine treatment also enhanced the growth, motility, and invasion of macrophages. Mechanistic studies revealed increased phosphorylation of STAT3 in nicotine-treated macrophages that was mediated through Src activation. Importantly, pretreatment of macrophages with either Src or STAT3 inhibitor abrogated nicotine-induced macrophage polarization, growth, and motility, suggesting a functional role of the Src-STAT3 signaling axis. Together, our findings reveal a novel role of nicotine in immunosuppression via causing M2 polarization of macrophages that could be implicated in the pathogenesis of various diseases.

MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer.

BACKGROUND: Aberrant activation of androgen receptor signalling following castration therapy is a common clinical observation in prostate cancer (PCa). Earlier, we demonstrated the role of MYB overexpression in androgen-depletion resistance and PCa aggressiveness. Here, we investigated MYB-androgen receptor (AR) crosstalk and its functional significance. METHODS: Interaction and co-localization of MYB and AR were examined by co-immunoprecipitation and immunofluorescence analyses, respectively. Protein levels were measured by immunoblot analysis and enzyme-linked immunosorbent assay. The role of MYB in ligand-independent AR transcriptional activity and combinatorial gene regulation was studied by promoter-reporter and chromatin immunoprecipitation assays. The functional significance of MYB in castration resistance was determined using an orthotopic mouse model. RESULTS: MYB and AR interact and co-localize in the PCa cells. MYB-overexpressing PCa cells retain AR in the nucleus even when cultured under androgen-deprived conditions. AR transcriptional activity is also sustained in MYB-overexpressing cells in the absence of androgens. MYB binds and promotes AR occupancy to the KLK3 promoter. MYB-overexpressing PCa cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to shorter mice survival, compared to those carrying low-MYB-expressing prostate tumours. CONCLUSIONS: Our findings reveal a novel MYB-AR crosstalk in PCa and establish its role in castration resistance.

Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy.

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.

Turning Adversity into Strength and Transferring It to the Uninitiated: The Tricks Cancer Cells Play to Survive Hypoxic Stress and Fight Chemotherapy.

Despite significant progress during the past few decades, cancer remains the second most common cause of death in the US after heart disease [...].

Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation.

Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3'UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells.

Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management.

Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer, contributing to the high mortality-to-incidence ratio. Management of the platinum-resistant disease has been difficult due to diverse underlying molecular mechanisms. Over the past several years, research has revealed several novel molecular targets that are being explored as biomarkers for treatment planning and monitoring of response. The therapeutic landscape of ovarian cancer is also rapidly evolving, and alternative therapies are becoming available for the recurrent platinum-resistant disease. This review provides a snapshot of platinum resistance mechanisms and discusses liquid-based biomarkers and their potential utility in effective management of platinum-resistant ovarian cancer.

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer.

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.

Extracellular Nanovesicles: From Intercellular Messengers to Efficient Drug Delivery Systems.

Nanosized extracellular vesicles (nEV) are released by all the eukaryotic cells into the extracellular spaces. They serve as crucial mediators of intercellular communication, and their presence has been detected in a variety of body fluids. nEV carry nucleic acids, lipids, proteins, and metabolites from the donor cells and transfer them to the recipient cells in the vicinity or distant locations to cause changes in their biological phenotypes. This very property of nEV makes them a suitable carrier of the drugs for therapeutic applications. The use of nEV as a drug delivery system offers several advantages over synthetic nanoparticles, including biocompatibility, natural targeting ability, and long-term safety. Further, nEV can be isolated from various biological sources, quickly loaded with the drug of choice, and modified to further enhance their utility as targeted drug delivery vehicles. Here we review these aspects of nEV and discuss the parameters that should be kept in mind while choosing the nEV source, drug loading method, and surface modification strategies. We also discuss the challenges associated with the nEV-based drug delivery platforms that must be overcome before realizing their full potential in clinical applications.

Exosomal Formulation Escalates Cellular Uptake of Honokiol Leading to the Enhancement of Its Antitumor Efficacy.

Honokiol is a phytochemical isolated from the Magnolia plant. It exhibits significant antitumor activity against a variety of cancer cell types via targeting of critical mediators of tumor progression, stromal remodeling, and chemoresistance. However, poor bioavailability and inefficient tumor uptake remain some of the hurdles in its translation as a therapeutically useful drug. Here, we developed a nanoformulation of honokiol using mesenchymal stem cell-derived exosomes, which are nonimmunogenic and express surface markers to support their tumor-targeted delivery. Maximum entrapment of honokiol occurred when it was mixed in a 1:4 weight ratio with exosomes and subjected to six cycles of sonication. Dynamic light scattering analysis demonstrated that the average size (∼175.3 nm), polydispersity (∼0.11), and integrity (∼12.9 mV) of exosomes remained in the desirable range post honokiol encapsulation. Exosome-encapsulated honokiol exhibited significantly higher therapeutic efficacy over the free honokiol in WST-1 growth and long-term clonogenicity assays. Flow cytometry-based cell cycle and live/dead cell assay, respectively, confirmed the enhanced effect of exosomal honokiol formulation on cell cycle arrest and apoptosis induction. More significant alterations in the expression of cell cycle- and survival-associated proteins were also observed in cancer cells treated with exosomal honokiol over free honokiol. Higher intracellular accumulation of honokiol was recorded in cancer cells treated with equivalent doses of honokiol as compared to the free honokiol. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved antitumor efficacy resulting from improved cellular uptake.

Comprehensive Analysis of Expression, Clinicopathological Association and Potential Prognostic Significance of RABs in Pancreatic Cancer.

RAB proteins (RABs) represent the largest subfamily of Ras-like small GTPases that regulate a wide variety of endosomal membrane transport pathways. Their aberrant expression has been demonstrated in various malignancies and implicated in pathogenesis. Using The Cancer Genome Atlas (TCGA) database, we analyzed the differential expression and clinicopathological association of RAB genes in pancreatic ductal adenocarcinoma (PDAC). Of the 62 RAB genes analyzed, five (RAB3A, RAB26, RAB25, RAB21, and RAB22A) exhibited statistically significant upregulation, while five (RAB6B, RAB8B, RABL2A, RABL2B, and RAB32) were downregulated in PDAC as compared to the normal pancreas. Racially disparate expression was also reported for RAB3A, RAB25, and RAB26. However, no clear trend of altered expression was observed with increasing stage and grade, age, and gender of the patients. PDAC from occasional drinkers had significantly higher expression of RAB21 compared to daily or weekly drinkers, whereas RAB25 expression was significantly higher in social drinkers, compared to occasional ones. The expression of RABL2A was significantly reduced in PDAC from diabetic patients, whereas RAB26 was significantly lower in pancreatitis patients. More importantly, a significant association of high expression of RAB21, RAB22A, and RAB25, and low expression of RAB6B, RABL2A, and RABL2B was observed with poorer survival of PC patients. Together, our study suggests potential diagnostic and prognostic significance of RABs in PDAC, warranting further investigations to define their functional and mechanistic significance.

Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer.

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.

Proteomic Analysis of MYB-Regulated Secretome Identifies Functional Pathways and Biomarkers: Potential Pathobiological and Clinical Implications.

Earlier we have shown important roles of MYB in pancreatic tumor pathobiology. To better understand the role of MYB in the tumor microenvironment and identify MYB-associated secreted biomarker proteins, we conducted mass spectrometry analysis of the secretome from MYB-modulated and control pancreatic cancer cell lines. We also performed in silico analyses to determine MYB-associated biofunctions, gene networks, and altered biological pathways. Our data demonstrated significant modulation (p < 0.05) of 337 secreted proteins in MYB-silenced MiaPaCa cells, whereas 282 proteins were differentially present in MYB-overexpressing BxPC3 cells, compared to their respective control cells. Alteration of several phenotypes such as cellular movement, cell death and survival, inflammatory response, protein synthesis, etc. was associated with MYB-induced differentially expressed proteins (DEPs) in secretomes. DEPs from MYB-silenced MiaPaCa PC cells were suggestive of the downregulation of genes primarily associated with glucose metabolism, PI3K/AKT signaling, and oxidative stress response, among others. DEPs from MYB-overexpressing BxPC3 cells suggested the enhanced release of proteins associated with glucose metabolism and cellular motility. We also observed that MYB positively regulated the expression of four proteins with potential biomarker properties, i.e., FLNB, ENO1, ITGB1, and INHBA. Mining of publicly available databases using Oncomine and UALCAN demonstrated that these genes are overexpressed in pancreatic tumors and associated with reduced patient survival. Altogether, these data provide novel avenues for future investigations on diverse biological functions of MYB, specifically in the tumor microenvironment, and could also be exploited for biomarker development.

Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities.

Altered cellular metabolism is a hallmark of cancer. Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways. Furthermore, altered metabolism is also reported in tumor-corrupted stromal cells as a result of their interaction with cancer cells or due to their adaptation in the dynamic tumor microenvironment. Metabolic alterations are associated with dysregulation of metabolic enzymes and tumor-stromal metabolic crosstalk is vital for the progressive malignant journey of the tumor cells. Therefore, several therapies targeting metabolic enzymes have been evaluated and/or are being investigated in preclinical and clinical studies. In this review, we discuss some important metabolic enzymes that are altered in tumor and/or stromal cells, and focus on their role in supporting tumor growth. Moreover, we also discuss studies carried out in various cancers to target these metabolic abnormalities for therapeutic exploitation.