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Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
Earl DC, Ferrell PB, Leelatian N, Froese JT, Reisman BJ, Irish JM, Bachmann BO
(2018) Nat Commun 9: 39
MeSH Terms: Aged, Bone Marrow, Cell Extracts, Chromatography, Liquid, DNA Damage, Female, Flow Cytometry, Humans, Leukemia, Leukemia, Myeloid, Acute, Lymphocytes, Male, Mass Spectrometry, Metabolome, Metabolomics, Monocytes, Signal Transduction, Streptomyces, Tumor Cells, Cultured, Young Adult
Show Abstract · Added January 4, 2018
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
3 Communities
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20 MeSH Terms
The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ.
Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J
(2017) Sci Signal 10:
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Transport System ASC, Animals, Biomarkers, Tumor, Breast Neoplasms, DNA-Binding Proteins, Disease Models, Animal, Ephrin-A2, Female, Glutaminase, Glutamine, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Minor Histocompatibility Antigens, Muscle Proteins, Phosphoproteins, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added April 2, 2019
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing or substantially reduced the amount of intracellular glutamate through decreased expression of and , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both and contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, expression positively correlated with that of and , as well as that of and Although high expression of predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective.
Chifman J, Arat S, Deng Z, Lemler E, Pino JC, Harris LA, Kochen MA, Lopez CF, Akman SA, Torti FM, Torti SV, Laubenbacher R
(2017) PLoS Comput Biol 13: e1005352
MeSH Terms: Adaptation, Physiological, Animals, Breast, Cell Transformation, Neoplastic, Computer Simulation, Epithelial Cells, Female, Humans, Iron, Iron Regulatory Protein 2, Models, Biological, Signal Transduction, Tumor Cells, Cultured, ras Proteins
Show Abstract · Added April 19, 2017
Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built.
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14 MeSH Terms
PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.
Roy N, Takeuchi KK, Ruggeri JM, Bailey P, Chang D, Li J, Leonhardt L, Puri S, Hoffman MT, Gao S, Halbrook CJ, Song Y, Ljungman M, Malik S, Wright CV, Dawson DW, Biankin AV, Hebrok M, Crawford HC
(2016) Genes Dev 30: 2669-2683
MeSH Terms: Acinar Cells, Animals, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Gene Deletion, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Mice, Pancreatic Neoplasms, Tissue Array Analysis, Trans-Activators, Tumor Cells, Cultured
Show Abstract · Added February 7, 2017
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.
© 2016 Roy et al.; Published by Cold Spring Harbor Laboratory Press.
2 Communities
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13 MeSH Terms
Covalent Modification of CDK2 by 4-Hydroxynonenal as a Mechanism of Inhibition of Cell Cycle Progression.
Camarillo JM, Rose KL, Galligan JJ, Xu S, Marnett LJ
(2016) Chem Res Toxicol 29: 323-32
MeSH Terms: Aldehydes, Cell Cycle Checkpoints, Cyclin-Dependent Kinase 2, Dose-Response Relationship, Drug, Humans, Models, Molecular, Structure-Activity Relationship, Tumor Cells, Cultured
Show Abstract · Added April 14, 2017
Oxidative stress is a contributing factor in a number of chronic diseases, including cancer, atherosclerosis, and neurodegenerative diseases. Lipid peroxidation that occurs during periods of oxidative stress results in the formation of lipid electrophiles, which can modify a multitude of proteins in the cell. 4-Hydroxy-2-nonenal (HNE) is one of the most well-studied lipid electrophiles and has previously been shown to arrest cells at the G1/S transition. Recently, proteomic data have shown that HNE is capable of covalently modifying CDK2, the kinase responsible for the G1/S transition. Here, we identify the sites adducted by HNE using recombinant CDK2 and show that HNE treatment suppresses the kinase activity of the enzyme. We further identify sites of adduction in HNE-treated intact human colorectal carcinoma cells (RKO) and show that HNE-dependent modification in cells is long-lived, disrupts CDK2 function, and correlates with a delay of progression of the cells into S-phase. We propose that adduction of CDK2 by HNE directly alters its activity, contributing to the cell cycle delay.
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8 MeSH Terms
Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.
Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM
(2015) Cancer 121: 4348-58
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Chemokine CXCL5, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, I-kappa B Kinase, In Vitro Techniques, Inflammation, Interleukin-1beta, Mice, Mice, Knockout, Peptides, Phosphorylation, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-4, Stomach, Stomach Neoplasms, Transcription Factor RelA, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added September 28, 2015
BACKGROUND - Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.
METHODS - For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.
RESULTS - The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.
CONCLUSIONS - These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.
© 2015 American Cancer Society.
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24 MeSH Terms
Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells.
Dravis C, Spike BT, Harrell JC, Johns C, Trejo CL, Southard-Smith EM, Perou CM, Wahl GM
(2015) Cell Rep 12: 2035-48
MeSH Terms: Animals, Breast Neoplasms, Cell Culture Techniques, Cell Differentiation, Epithelial Cells, Epithelial-Mesenchymal Transition, Female, Fetus, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Animal, Mammary Glands, Human, Mesenchymal Stem Cells, Mice, SOXE Transcription Factors, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added September 28, 2015
To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here, we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence whereas its overexpression increases stem/progenitor activity. Intriguingly, we also show that Sox10 overexpression causes mammary cells to undergo a mesenchymal transition. Consistent with these findings, Sox10 is preferentially expressed in stem- and mesenchymal-like breast cancers. These results demonstrate a signaling mechanism through which stem and mesenchymal states are acquired in mammary cells and suggest therapeutic avenues in breast cancers for which targeted therapies are currently unavailable.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Hover LD, Young CD, Bhola NE, Wilson AJ, Khabele D, Hong CC, Moses HL, Owens P
(2015) Cancer Lett 368: 79-87
MeSH Terms: Antineoplastic Agents, Bone Morphogenetic Protein Receptors, Bone Morphogenetic Proteins, Cell Proliferation, Cisplatin, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Ovarian Neoplasms, Pyrazoles, Quinolines, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added August 4, 2015
The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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4 Members
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16 MeSH Terms
Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation.
Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson RC, Sarkaria JN, Chen W, Lathia JD, Mobley BC, Clark SW, Wang J
(2016) Neuro Oncol 18: 48-57
MeSH Terms: Animals, Antigens, CD, Brain Neoplasms, Cell Proliferation, Cell Survival, Female, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Mice, Nude, Proto-Oncogene Proteins c-akt, Receptor, Insulin, Receptors, Somatomedin, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added July 23, 2015
BACKGROUND - Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
METHODS - In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
RESULTS - We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
CONCLUSIONS - Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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17 MeSH Terms