Mauricio J Reginato

Drexel University College of Medicine · Department of Biochemistry & Molecular Biology

Tumors utilize aerobic glycolysis to support growth and invasion. However, the molecular mechanisms that link metabolism with invasion are not well understood. The nutrient sensor O-linked-β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) modifies intracellular proteins with N-acetylglucosamine. Cancers display elevated O-GlcNAcylation and suppres...

The Hexosamine Biosynthetic Pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine and acetyl-CoA. Increased flux through HBP leads to elevated post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteri...

Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression...

Cancers exhibit altered metabolism characterized by increased glucose and glutamine uptake. The hexosamine biosynthetic pathway (HBP) utilizes glucose and glutamine, and directly contributes to O-linked-beta-N-acetylglucosamine (O-GlcNAc) modifications on intracellular proteins. Multiple tumor types contain elevated total O-GlcNAcylation, in part,...

The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked b-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-Glc...

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeli...

Breast-cancer brain metastasis (BCBM) poses a significant clinical challenge, resulting in an end-stage diagnosis and hindered by limited therapeutic options. The blood-brain barrier (BBB) acts as an anatomical and physiological hurdle for therapeutic compounds, restricting the effective delivery of therapies to the brain. In order to grow and surv...

Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-spec...

Introduction Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metab...

Breast cancer is the most common cancer and the second leading cause of cancer death among women overall. One of the main challenges in fighting breast cancer is the intratumor heterogeneity as they are composed of different subpopulations of cancer cells. This heterogeneity of breast cancer is promoted and maintained by a subpopulation of cancer s...

Brain metastases (BMs) in breast cancer patients is considered an end-stage event, with no effective drug treatment and a median survival after diagnosis measured in months. Currently, there are no effective drug treatment for BM patients, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the bra...

Brain metastases (BMs) in breast cancer patients is considered an end-stage event, with no effective drug treatment and a median survival after diagnosis measured in months. Currently, there are no effective drug treatment for BM patients, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the bra...

Tumor growth and metastasis can be promoted by a small sub-population of cancer cells, termed cancer stem-like cells (CSCs). While CSCs possess capability in self-renewing and differentiating, the hierarchy of CSCs during tumor growth is highly plastic. This plasticity in CSCs fate and function can be regulated by signals from the tumor microenviro...

One of the main challenges in treating breast cancer is the intra-tumor heterogeneity, which, partly, is maintained and promoted by a sub-population of breast cancer cells called breast cancer stem-like cells (BCSCs). BCSCs shares traits of mammary stem cells, capable of self-renewing and differentiating, while promotes invasion, metastasis, drug r...

Onset of brain metastases (BMs) in breast cancer patients is considered an end-stage event, with no effective drug treatment and a median survival after diagnosis measured in months. Thus, there is an urgent need to develop novel treatment strategies. Metastatic breast cancer cells colonizing the brain encounter adverse 'nutritional environment', a...

Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-...

O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA which catalyze the addition or removal of the UDP-GlcNAc moieties, respectively. Structural changes brought by this modification lead to alternations of protein stability, protein-prote...

One of the main challenges in treating breast cancer is the intra-tumor heterogeneity, which, partly, is maintained and promoted by a sub-population of breast cancer cells called breast cancer stem-like cells (BCSCs). BCSCs shares traits of mammary stem cells, capable of self-renewing and differentiating, while promotes invasion, metastasis, drug r...

Cancer cells alter their metabolism to increase cell growth. A subset of the glucose taken up is shunted into the hexosamine biosynthetic pathway where it is used to synthesize UDP-GlcNAc, a substrate of O-GlcNAc transferase (OGT), which modifies cytoplasmic and nuclear proteins with O-linked sugar moieties. Here, we show that OGT and O-GlcNAcylati...

Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-...

Cancer stem cells (CSCs) make up part of the heterogenous tumor bulk that plays a critical role in tumor cell growth and metastasis. Similar to adult stem cells, CSCs are capable of self-renewing and differentiating, resulting in bulk tumor growth, metastases and therapeutic resistance. The functions of CSCs are regulated by numerous pathways. One...

Breast tumors are heterogeneous and composed of different subpopulation of cells, each with dynamic roles that can change with stage, site, and microenvironment. Cellular heterogeneity is, in part, due to cancer stem–like cells (CSC) that share properties with stem cells and are associated with treatment resistance. CSCs rewire metabolism to meet e...

Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary drivers of tumor growth and act as substrates for the hexosamine biosynthetic pathway (HBP). The HBP culminates in the production of an amino sugar uridine diphosphate N-acetylglucosam...

Elevated O-GlcNAcylation is emerging as a general characteristic of most cancers. Although O-GlcNAcylation can regulate many cell biological pathways, recent evidence suggests that it is a key regulator of metabolic pathways including glycolysis in cancer cells. This review summarizes our current understanding of how O-GlcNAcylation regulates glyco...

Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master l...

Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in T...

In breast cancer the use of small molecule inhibitors of tyrosine kinase activity of the ERBB family members improves survival thus represents a valuable therapeutic strategy. The addition of calcitriol, the most active metabolite of vitamin D, or some of its analogs, to conventional anticancer drugs, including tyrosine kinase inhibitors (TKIs), ha...

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearing TSC2 mutations migrate to the lungs, proliferate, and cause cystic remodeling. The female predominance indicates that estrogen plays a critical role in LAM pathogenesis, and we have proposed that estrogen...

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearing TSC2 mutations migrate to the lungs, proliferate, and cause cystic remodeling. The female predominance indicates that estrogen plays a critical role in LAM pathogenesis, and we have proposed that estrogen...

The Warburg hypothesis states that cancer cells display altered metabolic features to support their rapid growth and biosynthetic demands including increased glycolytic flux to synthesize necessary building blocks required by growing cells. Increased glucose uptake feeds not only glycolysis but other glucose dependent pathways as well, such as the...

Overexpression/amplification of the tyrosine kinase ErbB2 is often observed in breast cancers. ErbB2 expression activates EGFR signaling pathway promoting tumorigenesis. Breast cancer ErbB2-positive patients are treated with lapatinib, a dual EGFR/ERBB2 inhibitor. Despite lapatinib clinical efficacy, acquired resistance has been reported and its me...

Glioblastoma (GBM) is the most malignant type of brain tumor, its therapy hindered by the hypoxic microenvironment that promotes tumor resistance and inhibits immune cell function. We propose combining dendritic cell (DC) immunotherapy with hypoxia reversal to eradicate GBM. HIF-1α, a transcription factor that stimulates genes promoting angiogenesi...

Major advances in the genomics and epigenomics of diffuse gliomas and glioblastoma to date have not been translated into effective therapy, necessitating pursuit of alternative treatment approaches for these therapeutically challenging tumors. Current knowledge of microtubules in cancer and the development of new microtubule-based treatment strateg...

Increased O-GlcNAcylation is emerging as a general characteristic of cancer cells that is critical for multiple oncogenic phenotypes. Recently, we demonstrated that elevated O-GlcNAcylation contributes to the metabolic shift seen in cancer through stabilization of the glycolytic regulator HIF-1a and links metabolism to stress and cancer cell surviv...

A variety of mechanotransduction forces are altered in the tumor microenvironment (TME) and these biophysical forces can influence cancer progression. One such force is interstitial fluid flow (IFF) - the movement of fluid through the tissue matrix. IFF was previously shown to induce invasion of cancer cells, but the activated signaling cascades re...

ERBB2/HER2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can promote tumor progression. Breast cancer patients with ERBB2 amplifications are currently treated with lapatinib, a small-molecule kinase inhibitor that specifically blocks EGFR/ERBB2 signaling. Here, we show that hypoxia, via HIF-1, induces resistance to...

Cancer cells exhibit a unique metabolic shift to aerobic glycolysis that has been exploited diagnostically and therapeutically in the clinic. Oncogenes and tumor suppressors alter signaling pathways that lead to alterations of glycolytic flux. Stemming from glycolysis, the hexosamine biosynthetic pathway leads to elevated posttranslational addition...

Breast cancer is one of the most common cancers among women. Many factors are associated with this disease including overexpression/amplification of the tyrosine kinase HER2/ErbB2. ErbB2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can activate multiple signaling pathways that can promote tumor progression via regu...

Glioblastoma multiforme (GBM) is the most malignant type of brain tumor with a mean survival time of one year. The most difficult problem to treat tumors is their hypoxic microenvironment that changes the phenotypic characteristic of immune cells. In hypoxic conditions, HIF-1α, a transcription factor, accumulates and stimulates various genes that p...

O-linked glycans on plasma membrane proteins are altered in cancer cells, leading to changes in cell adhesive properties and contributing to metastasis. Mechanisms of how these carbohydrates alter tumor spread remain vague. In this issue of Cancer Discovery, Murugaesu and colleagues, using an in vivo functional RNA interference metastasis screen, i...

HER2/Neu/ERBB2 is a receptor tyrosine kinase overexpressed in approximately 20% of human breast tumors. Truncated or mutant isoforms which show increased oncogenicity compared to the wild-type receptor are found in many breast tumors. Here we report that constitutively active ERBB2 sensitizes human breast epithelial cells to agents that induce endo...

Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs); however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation...

ERBB2, a receptor tyrosine kinase amplified in breast cancer, is a well established regulator of tumor growth in vivo and anoikis resistance leading to disruption of architecture in three-dimensional mammary epithelial acinar structures in vitro. ERBB2 promotes anoikis resistance by maintaining signaling pathways and by rescuing metabolic defects a...

Pancreatic ductal adenocarcinoma (PDAC) commonly contains a mutation in K-Ras (G12D) and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM). Our previous observations imply that inhibiting the mitogen-activated protein kinase (MAPK)-extracellular signal-regulat...

Pancreatic ductal adenocarcinoma (PDAC) commonly contains a mutation in K-Ras(G12D) and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM). Our previous observations imply that inhibiting the mitogen-activated protein kinase (MAPK)-extracellular signal-regulate...

ErbB2 is frequently highly expressed in premalignant breast cancers, including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it contributes to progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here, we show that clinical...

Increased activation of the epidermal growth factor receptor (EGFR) is frequently observed in tumors, and inhibition of the signaling pathways originated in the EGFR normally renders tumor cells more sensitive to apoptotic stimuli. However, we show that inhibition of EGFR signaling in non-transformed breast epithelial cells by EGF deprivation or ge...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL ErbB2 is frequently amplified in premalignant breast cancers including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it modulates in the progression into the invasive/malignant state. Radiotherapy is often used to treat early pre...

Active glutamine utilization is essential for cell proliferation in many tumors, for it provides critical carbon and nitrogen sources. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase. Previous studies have shown that c-Myc regulates glutaminolysis by increasing glutaminase expressi...

Pancreatic ductal adenocarcinomas (PDAC) are highly invasive & metastatic neoplasms unresponsive to current therapies. Overwhelmingly, PDAC harbors constitutive, oncogenic mutations in K‐ Ras G12D that exist prior to invasion. Histologic & genetic analyses of human PDAC exhibit increased expression of ERK1/2 and pro‐invasive MMPs; indicators of poo...

Cancer cells universally increase glucose and glutamine consumption, leading to the altered metabolic state known as the Warburg effect; one metabolic pathway, highly dependent on glucose and glutamine, is the hexosamine biosynthetic pathway. Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translational add...

Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-Ras(G12D) that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellul...

Tumor hypoxia correlates with resistance to chemotherapy, increased incidence of metastasis and poor clinical prognosis. Early breast cancer lesions, such as carcinoma in situ, characterized by filled lumens, are often associated with hypoxic markers. However, the contribution of hypoxia to changes in tissue architecture in early pre-malignant lesi...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Cancer cells universally increase glucose and glutamine consumption, leading to the altered metabolic state known as the Warburg effect. One metabolic pathway highly dependent on glucose and glutamine is the Hexosamine Biosynthetic Pathway (HBP). Increased flux through the HB...

Comment on: Caldwell SA, et al. Oncogene 2010; 29:2831-42.

Proper adhesion to extracellular matrix is critical for epithelial cell survival. Detachment from matrix signals results in apoptosis, referred to as anoikis. Selective apoptosis of cells that become detached from matrix is associated with the formation of a lumen in three-dimensional mammary epithelial acinar structures in vitro. Because early bre...

Strong evidences support the inhibitory activity of cellular FLICE-inhibitory protein (FLIP) in the apoptotic signalling by death receptors in tumor cells. However, little is known about the role of FLIP in the regulation of apoptosis in non-transformed cells. In this report, we demonstrate that FLIP(L) plays an important role as a survival protein...

Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. Approximately 2-5% of a cell's glucose enters the hexosamine biosynthetic pathway (HBP) which regulates levels of O-linked beta-N-acetylglucosamine (O-GlcNAc), a carbohydrate post-translational modification of diverse nuclear and cytosolic proteins. We have discover...

Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway (HBP), which regulates levels of O-linked beta-N-acetylglucosamine (O-GlcNAc), a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins. We discovered that...

ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, w...

An important aspect of cancer biology is cell migration, which is often mediated by chemical gradients in the environment. Three-dimensional (3D) epithelial culture models utilizing biological based matrices such as Matrigel (a popular biomatrix hydrogel) provide a more physiologically relevant setting for studying cancer cell migration. In this pa...

Three-dimensional (3D) epithelial culture models are widely used to promote a physiologically relevant microenvironment for the study of normal and aberrant epithelial organization. Despite the increased use of these models, their potential as a cell-based screening tool for therapeutics has been hindered by the lack of existing platforms for large...

The lumens present in ductal structures are required for transport of fluids and air. Studies in model organisms and cells in culture suggest that lumens can be generated by multiple mechanisms including apoptosis of centrally located cells, and re-modeling of epithelia. Several studies point to a role for apoptosis during lumen formation in the ma...

We reported earlier that IL-1beta, an NF-kappaB-regulated cytokine, was made by intestinal epithelial cells during detachment-induced apoptosis (anoikis) and that IL-1 was antiapoptotic for detached cells. Since surviving anoikis is a prerequisite for cancer progression and metastases, we are further exploring the link between anoikis and cytokines...

Proper attachment to the extracellular matrix is essential for cell survival. Detachment from the extracellular matrix results in an apoptotic process termed anoikis. Anoikis induction in MCF-10A mammary epithelial cells is due not only to loss of survival signals following integrin disengagement, but also to consequent downregulation of epidermal...

Epithelial cells organize into cyst-like structures that contain a spherical monolayer of cells that enclose a central lumen. Using a three-dimensional basement membrane culture model in which mammary epithelial cells form hollow, acinus-like structures, we previously demonstrated that lumen formation is achieved, in part, through apoptosis of cent...

Many mouse models of breast cancer form large primary tumors that rarely metastasize. Models with aggressive metastasis express oncoproteins that simultaneously affect growth and apoptosis pathways. To define the role of apoptotic resistance and to model a challenge faced by tumor cells during metastatic dissemination, we focused on apoptosis induc...

The molecular events regulating the elimination of cells to create a hollow lumen during tissue development are poorly understood. By using an in vitro morphogenesis model in which MCF-10A human mammary epithelial cells form hollow acini-like structures, we have observed both caspase-mediated apoptosis and autophagy associated with cells that are l...

Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis. Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival. Recent evidence suggests that integrin receptors are coupled to growth factor receptors in t...

We have utilized in vitro three-dimensional epithelial cell cultures to analyze the role of apoptosis in the formation and maintenance of a hollow glandular architecture. Lumen formation is associated with the selective apoptosis of centrally located cells; this apoptosis follows apicobasal polarization and precedes proliferative suppression during...

Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is expressed predominantly...

Thiazolidinediones (TZDs) constitute an exciting new class of antidiabetic compounds, which function as activating ligands for peroxisome proliferator-activated receptor γ (PPARγ). Until now, there has been an excellent correlation between in vivo hypoglycemic potency and in vitro binding and activation of PPARγ by TZDs. We have characterized MCC-5...

Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implic...

Fat cell differentiation is a critical aspect of obesity and diabetes. Dietary fatty acids are converted to arachidonic acid, which serves as precursor of prostaglandins (PGs). PGJ2 derivatives function as activating ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor that is central to adipogenic d...

Thyroid hormone (T3) and retinoic acid (RA) play important roles in erythropoiesis. We found that the hematopoietic cell-specific bZip protein p45/NF-E2 interacts with T3 receptor (TR) and RA receptor (RAR) but not retinoid X receptor. The interaction is between the DNA-binding domain of the nuclear receptor and the leucine zipper region of p45/NF-...

Adipocyte differentiation is thought to involve sequential induction of the transcription factors C/EBPbeta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBPalpha. C/EBPalpha expression is both necessary and sufficient for adipocyte differentiation. Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta indu...

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates transcription in response to prostanoid and thiazolidinedione ligands and promotes adipocyte differentiation. The amino-terminal A/B domain of this receptor contains a consensus mitogen-activated protein kinase site in a region common to PPARγ1 and -γ2 isoforms. The...

Thyroid hormone receptors (TRs) require heterodimerization with retinoid X receptor (RXR) for maximum DNA binding affinity. Interaction with RXR occurs via two dimerization interfaces, one in the DNA-binding domain and one in the C-terminal "ninth heptad" of the receptors. We studied the relative importance of these two dimerization domains in natu...

The thyroid hormone (T3) receptor (TR) variant TR alpha 2 is abundant in brain but does not bind T3 because of its unique C terminus. The only known function of TR alpha 2, inhibition of TR-dependent transactivation, involves competition for T3 response elements. Paradoxically, in vitro-translated TR alpha 2 bound poorly to these sites. We report h...