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153. Mechanosensing by the Lamina Protects against Nuclear Rupture, DNA Damage, and Cell-Cycle Arrest

Author

Cho, Sangkyun, primary, Vashisth, Manasvita, additional, Abbas, Amal, additional, Majkut, Stephanie, additional, Vogel, Kenneth, additional, Xia, Yuntao, additional, Ivanovska, Irena L., additional, Irianto, Jerome, additional, Tewari, Manorama, additional, Zhu, Kuangzheng, additional, Tichy, Elisia D., additional, Mourkioti, Foteini, additional, Tang, Hsin-Yao, additional, Greenberg, Roger A., additional, Prosser, Benjamin L., additional, and Discher, Dennis E., additional

Published
2019
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154. ARID1A spatially partitions interphase chromosomes

Author

Wu, Shuai, primary, Fatkhutdinov, Nail, additional, Rosin, Leah, additional, Luppino, Jennifer M., additional, Iwasaki, Osamu, additional, Tanizawa, Hideki, additional, Tang, Hsin-Yao, additional, Kossenkov, Andrew V., additional, Gardini, Alessandro, additional, Noma, Ken-ichi, additional, Speicher, David W., additional, Joyce, Eric F., additional, and Zhang, Rugang, additional

Published
2019
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155. NAD+ metabolism governs the proinflammatory senescence-associated secretome

Author

Nacarelli, Timothy, primary, Lau, Lena, additional, Fukumoto, Takeshi, additional, Zundell, Joseph, additional, Fatkhutdinov, Nail, additional, Wu, Shuai, additional, Aird, Katherine M., additional, Iwasaki, Osamu, additional, Kossenkov, Andrew V., additional, Schultz, David, additional, Noma, Ken-ichi, additional, Baur, Joseph A., additional, Schug, Zachary, additional, Tang, Hsin-Yao, additional, Speicher, David W., additional, David, Gregory, additional, and Zhang, Rugang, additional

Published
2019
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157. ThG Cells: A Distinct T Helper Cell Subset with Lineage Characteristics

Author

Rasouli, Javad, primary, Casella, Giacomo, additional, Yoshimura, Satoshi, additional, Zhang, Weifeng, additional, Xiao, Dan, additional, Kumar, Gaurav, additional, Garifallou, James, additional, Gonzalez, Michael V., additional, Wiedeman, Alice, additional, Mari, Elisabeth R., additional, Tang, Hsin-Yao, additional, Fortina, Paolo, additional, Hakonarson, Hakon, additional, Long, Alice, additional, Zhang, Guang-Xian, additional, Ciric, Bogoljub, additional, and Rostami, Abdolmohamad, additional

Published
2019
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158. Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility

Author

Kaur, Amanpreet, primary, Ecker, Brett L., additional, Douglass, Stephen M., additional, Kugel, Curtis H., additional, Webster, Marie R., additional, Almeida, Filipe V., additional, Somasundaram, Rajasekharan, additional, Hayden, James, additional, Ban, Ehsan, additional, Ahmadzadeh, Hossein, additional, Franco-Barraza, Janusz, additional, Shah, Neelima, additional, Mellis, Ian A., additional, Keeney, Frederick, additional, Kossenkov, Andrew, additional, Tang, Hsin-Yao, additional, Yin, Xiangfan, additional, Liu, Qin, additional, Xu, Xiaowei, additional, Fane, Mitchell, additional, Brafford, Patricia, additional, Herlyn, Meenhard, additional, Speicher, David W., additional, Wargo, Jennifer A., additional, Tetzlaff, Michael T., additional, Haydu, Lauren E., additional, Raj, Arjun, additional, Shenoy, Vivek, additional, Cukierman, Edna, additional, and Weeraratna, Ashani T., additional

Published
2019
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159. Stromal changes in the aged lung induce an emergence from melanoma dormancy

Author

Fane, Mitchell E., Chhabra, Yash, Alicea, Gretchen M., Maranto, Devon A., Douglass, Stephen M., Webster, Marie R., Rebecca, Vito W., Marino, Gloria E., Almeida, Filipe, Ecker, Brett L., Zabransky, Daniel J., Hüser, Laura, Beer, Thomas, Tang, Hsin-Yao, Kossenkov, Andrew, Herlyn, Meenhard, Speicher, David W., Xu, Wei, Xu, Xiaowei, Jaffee, Elizabeth M., Aguirre-Ghiso, Julio A., and Weeraratna, Ashani T.

Abstract

Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1–3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4–8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.

Published
2022
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160. An Interleukin-23-Interleukin-22 Axis Regulates Intestinal Microbial Homeostasis to Protect from Diet-Induced Atherosclerosis

Author

Fatkhullina, Aliia R., primary, Peshkova, Iuliia O., additional, Dzutsev, Amiran, additional, Aghayev, Turan, additional, McCulloch, John A., additional, Thovarai, Vishal, additional, Badger, Jonathan H., additional, Vats, Ravi, additional, Sundd, Prithu, additional, Tang, Hsin-Yao, additional, Kossenkov, Andrew V., additional, Hazen, Stanley L., additional, Trinchieri, Giorgio, additional, Grivennikov, Sergei I., additional, and Koltsova, Ekaterina K., additional

Published
2018
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161. Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements.

Author

Seo, Jae Ho, Agarwal, Ekta, Bryant, Kelly G., Caino, M. Cecilia, Kim, Eui Tae, Kossenkov, Andrew V., Tang, Hsin-Yao, Languino, Lucia R., Gabrilovich, Dmitry I., Cohen, Andrew R., Speicher, David W., Altieri, Dario C., Seo, Jae Ho, Agarwal, Ekta, Bryant, Kelly G., Caino, M. Cecilia, Kim, Eui Tae, Kossenkov, Andrew V., Tang, Hsin-Yao, Languino, Lucia R., Gabrilovich, Dmitry I., Cohen, Andrew R., Speicher, David W., and Altieri, Dario C.

Abstract

Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. SNPH ubiquitination did not result in protein degradation, but instead anchored SNPH on tubulin to inhibit mitochondrial motility and cycles of organelle fusion and fission, that is dynamics. Expression of ubiquitination-defective SNPH mutant Lys111!Arg or Lys153!Arg increased the speed and distance traveled by mitochondria, repositioned mitochondria to the cortical cytoskeleton, and supported heightened tumor chemotaxis, invasion, and metastasis in vivo. Interference with SNPH ubiquitination activated mitochondrial dynamics, resulting in increased recruitment of the fission regulator dynamin-related protein-1 (Drp1) to mitochondria and Drp1-dependent tumor cell motility. These data uncover nondegradative ubiquitination of SNPH as a key regulator of mitochondrial trafficking and tumor cell motility and invasion. In this way, SNPH may function as a unique, ubiquitination-regulated suppressor of metastasis.

Published
2018

162. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.

Author

Singh, Kumar Sachin, Sharma, Rishabh, Reddy, Poli Adi Narayana, Vonteddu, Prashanthi, Good, Madeline, Sundarrajan, Anjana, Choi, Hyeree, Muthumani, Kar, Kossenkov, Andrew, Goldman, Aaron R., Tang, Hsin-Yao, Totrov, Maxim, Cassel, Joel, Murphy, Maureen E., Somasundaram, Rajasekharan, Herlyn, Meenhard, Salvino, Joseph M., and Dotiwala, Farokh

Abstract

Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations. A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]

Published
2021
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163. Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy.

Author

Jiao, Xuanmao, Wang, Min, Zhang, Zhao, Li, Zhiping, Ni, Dong, Ashton, Anthony W., Tang, Hsin-Yao, Speicher, David W., and Pestell, Richard G.

Subjects
TRIPLE-negative breast cancer, MONOCLONAL antibodies, CELL death, DNA damage, G protein coupled receptors, CD20 antigen
Abstract

Background: Triple-negative breast cancer (BCa) (TNBC) is a deadly form of human BCa with limited treatment options and poor prognosis. In our prior analysis of over 2200 breast cancer samples, the G protein-coupled receptor CCR5 was expressed in > 95% of TNBC samples. A humanized monoclonal antibody to CCR5 (leronlimab), used in the treatment of HIV-infected patients, has shown minimal side effects in large patient populations.Methods: A humanized monoclonal antibody to CCR5, leronlimab, was used for the first time in tissue culture and in mice to determine binding characteristics to human breast cancer cells, intracellular signaling, and impact on (i) metastasis prevention and (ii) impact on established metastasis.Results: Herein, leronlimab was shown to bind CCR5 in multiple breast cancer cell lines. Binding of leronlimab to CCR5 reduced ligand-induced Ca+ 2 signaling, invasion of TNBC into Matrigel, and transwell migration. Leronlimab enhanced the BCa cell killing of the BCa chemotherapy reagent, doxorubicin. In xenografts conducted with Nu/Nu mice, leronlimab reduced lung metastasis of the TNBC cell line, MB-MDA-231, by > 98% at 6 weeks. Treatment with leronlimab reduced the metastatic tumor burden of established TNBC lung metastasis.Conclusions: The safety profile of leronlimab, together with strong preclinical evidence to both prevent and reduce established breast cancer metastasis herein, suggests studies of clinical efficacy may be warranted. [ABSTRACT FROM AUTHOR]

Published
2021
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164. Short prolactin isoforms are expressed in photoreceptors of canine retinas undergoing retinal degeneration.

Author

Sudharsan, Raghavi, Murgiano, Leonardo, Tang, Hsin-Yao, Olsen, Timothy W., Chavali, Venkata R. M., Aguirre, Gustavo D., and Beltran, William A.

Subjects
PROLACTIN, PHOTORECEPTORS, RETINAL degeneration, TRANSCRIPTOMES, MESSENGER RNA
Abstract

Prolactin (PRL) hormone functions as a pleiotropic cytokine with a protective role in the retina. We recently identified by transcriptome profiling that PRL is one of the most highly upregulated mRNAs in the retinas of mutant rcd1 (PDE6B) and xlpra2 (RPGR) dogs at advanced stages of photoreceptor disease. In the present study, we have identified the expression of a short PRL isoform that lacks exon 1 in canine retinas and analyzed the time-course of expression and localization of this isoform in the retinas of these two models. Using laser capture microdissection to isolate RNA from each of the retinal cellular layers, we found by qPCR that this short PRL isoform is expressed in photoreceptors of degenerating retinas. We confirmed by in situ hybridization that its expression is localized to the outer nuclear layer and begins shortly after the onset of disease at the time of peak photoreceptor cell death in both models. PRL protein was also detected only in mutant dog retinas. Our results call for further investigations into the role of this novel PRL isoform in retinal degeneration. [ABSTRACT FROM AUTHOR]

Published
2021
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165. MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.

Author

Casciano, Jessica C., Perry, Caroline, Cohen-Nowak, Adam J., Miller, Katelyn D., Vande Voorde, Johan, Zhang, Qifeng, Chalmers, Susan, Sandison, Mairi E., Liu, Qin, Hedley, Ann, McBryan, Tony, Tang, Hsin-Yao, Gorman, Nicole, Beer, Thomas, Speicher, David W., Adams, Peter D., Liu, Xuefeng, Schlegel, Richard, McCarron, John G., and Wakelam, Michael J. O.

Abstract

Background: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood.Methods: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC.Results: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients.Conclusion: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype. [ABSTRACT FROM AUTHOR]

Published
2020
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166. Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence.

Author

Zhao, Bo, Liu, Pingyu, Fukumoto, Takeshi, Nacarelli, Timothy, Fatkhutdinov, Nail, Wu, Shuai, Lin, Jianhuang, Aird, Katherine M., Tang, Hsin-Yao, Liu, Qin, Speicher, David W., and Zhang, Rugang

Subjects
DNA topoisomerase I, PATTERN recognition systems, CELLULAR aging, IMMUNE recognition, ACTIVE aging, CHROMATIN, PROGRAMMED cell death 1 receptors, INFLAMMATION
Abstract

Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade. Here, the authors show that the topoisomerase 1-DNA covalent cleavage complex plays a critical role in mediating cytoplasmic chromatin fragments recognition by cyclic GMP-AMP synthase during senescence. The proposed axis is crucial to promote the inflammatory senescence-associated secretory phenotype and to enable the response to immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Published
2020
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168. Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer

Author

Lu, Huimin, primary, Bowler, Nicholas, additional, Harshyne, Larry A., additional, Craig Hooper, D., additional, Krishn, Shiv Ram, additional, Kurtoglu, Senem, additional, Fedele, Carmine, additional, Liu, Qin, additional, Tang, Hsin-Yao, additional, Kossenkov, Andrew V., additional, Kelly, William K., additional, Wang, Kerith, additional, Kean, Rhonda B., additional, Weinreb, Paul H., additional, Yu, Lei, additional, Dutta, Anindita, additional, Fortina, Paolo, additional, Ertel, Adam, additional, Stanczak, Maria, additional, Forsberg, Flemming, additional, Gabrilovich, Dmitry I., additional, Speicher, David W., additional, Altieri, Dario C., additional, and Languino, Lucia R., additional

Published
2018
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170. Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements

Author

Seo, Jae Ho, primary, Agarwal, Ekta, additional, Bryant, Kelly G., additional, Caino, M. Cecilia, additional, Kim, Eui Tae, additional, Kossenkov, Andrew V., additional, Tang, Hsin-Yao, additional, Languino, Lucia R., additional, Gabrilovich, Dmitry I., additional, Cohen, Andrew R., additional, Speicher, David W., additional, and Altieri, Dario C., additional

Published
2018
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171. Abstract 1441: MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cells

Author

Casciano, Jessica C., primary, Cohen-Nowak, Adam, additional, Voorde, Johan Vande, additional, Zhang, Qifeng, additional, Chalmers, Susan, additional, Sandison, Mairi, additional, Hedley, Ann, additional, McBryan, Tony, additional, Beer, Thomas, additional, Tang, Hsin-Yao, additional, Speicher, David W., additional, Adams, Peter, additional, Liu, Xiufeng, additional, Schlegel, Richard, additional, McCarron, John, additional, Wakelam, Michael J., additional, Gottlieb, Eyal, additional, and Schug, Zachary T., additional

Published
2018
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173. Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

Author

Bhattacharjee, Souvik, primary, Coppens, Isabelle, additional, Mbengue, Alassane, additional, Suresh, Niraja, additional, Ghorbal, Mehdi, additional, Slouka, Zdenek, additional, Safeukui, Innocent, additional, Tang, Hsin-Yao, additional, Speicher, David W., additional, Stahelin, Robert V., additional, Mohandas, Narla, additional, and Haldar, Kasturi, additional

Published
2018
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175. RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

Author

Singh, Kumar Sachin, Sharma, Rishabh, Reddy, Poli Adi Narayana, Vonteddu, Prashanthi, Good, Madeline, Sundarrajan, Anjana, Choi, Hyeree, Muthumani, Kar, Kossenkov, Andrew, Goldman, Aaron R., Tang, Hsin-Yao, Totrov, Maxim, Cassel, Joel, Murphy, Maureen E., Somasundaram, Rajasekharan, Herlyn, Meenhard, Salvino, Joseph M., and Dotiwala, Farokh

Abstract

Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacteriumand Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.

Published
2021
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178. Proteomic Analysis of Pemphigus Autoantibodies Indicates a Larger, More Diverse, and More Dynamic Repertoire than Determined by B Cell Genetics

Author

Chen, Jing, primary, Zheng, Qi, additional, Hammers, Christoph M., additional, Ellebrecht, Christoph T., additional, Mukherjee, Eric M., additional, Tang, Hsin-Yao, additional, Lin, Chenyan, additional, Yuan, Huijie, additional, Pan, Meng, additional, Langenhan, Jana, additional, Komorowski, Lars, additional, Siegel, Don L., additional, Payne, Aimee S., additional, and Stanley, John R., additional

Published
2017
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179. Uncovering Thousands of New Peptides with Sequence-Mask-Search Hybrid De NovoPeptide Sequencing Framework

Author

Karunratanakul, Korrawe, Tang, Hsin-Yao, Speicher, David W., Chuangsuwanich, Ekapol, and Sriswasdi, Sira

Abstract

De novopeptide sequencing is a promising approach for discovering new peptides. However, its performance is hindered by the fact that most MS/MS spectra do not contain complete amino acid sequence information. Here, we present a deep learning-based de novosequencing model, SMSNet, together with a post-processing strategy that pinpoints misidentified residues and utilizes user-provided sequence database to revise the identifications. The results show that many new HLA antigens and phosphopeptides can be discovered with our strategy.

Published
2019
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180. Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming.

Author

Chae, Young Chan, Vaira, Valentina, Caino, M. Cecilia, Tang, Hsin-Yao, Seo, Jae Ho, Kossenkov, Andrew V., Ottobrini, Luisa, Martelli, Cristina, Lucignani, Giovanni, Bertolini, Irene, Locatelli, Marco, Bryant, Kelly G., Ghosh, Jagadish C., Lisanti, Sofia, Ku, Bonsu, Bosari, Silvano, Languino, Lucia R., Speicher, David W., Altieri, Dario C., Chae, Young Chan, Vaira, Valentina, Caino, M. Cecilia, Tang, Hsin-Yao, Seo, Jae Ho, Kossenkov, Andrew V., Ottobrini, Luisa, Martelli, Cristina, Lucignani, Giovanni, Bertolini, Irene, Locatelli, Marco, Bryant, Kelly G., Ghosh, Jagadish C., Lisanti, Sofia, Ku, Bonsu, Bosari, Silvano, Languino, Lucia R., Speicher, David W., and Altieri, Dario C.

Abstract

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.

Published
2016

181. The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis.

Author

Seo, Jae Ho, Rivadeneira, Dayana B., Caino, M. Cecilia, Chae, Young Chan, Speicher, David W., Tang, Hsin-Yao, Vaira, Valentina, Bosari, Silvano, Palleschi, Alessandro, Rampini, Paolo, Kossenkov, Andrew V., Languino, Lucia R., Altieri, Dario C., Seo, Jae Ho, Rivadeneira, Dayana B., Caino, M. Cecilia, Chae, Young Chan, Speicher, David W., Tang, Hsin-Yao, Vaira, Valentina, Bosari, Silvano, Palleschi, Alessandro, Rampini, Paolo, Kossenkov, Andrew V., Languino, Lucia R., and Altieri, Dario C.

Abstract

Mitochondria must buffer the risk of proteotoxic stress to preserve bioenergetics, but the role of these mechanisms in disease is poorly understood. Using a proteomics screen, we now show that the mitochondrial unfoldase-peptidase complex ClpXP associates with the oncoprotein survivin and the respiratory chain Complex II subunit succinate dehydrogenase B (SDHB) in mitochondria of tumor cells. Knockdown of ClpXP subunits ClpP or ClpX induces the accumulation of misfolded SDHB, impairing oxidative phosphorylation and ATP production while activating "stress" signals of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy. Deregulated mitochondrial respiration induced by ClpXP targeting causes oxidative stress, which in turn reduces tumor cell proliferation, suppresses cell motility, and abolishes metastatic dissemination in vivo. ClpP is universally overexpressed in primary and metastatic human cancer, correlating with shortened patient survival. Therefore, tumors exploit ClpXP-directed proteostasis to maintain mitochondrial bioenergetics, buffer oxidative stress, and enable metastatic competence. This pathway may provide a "drugable" therapeutic target in cancer.

Published
2016

182. Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Author

Chae, Young Chan, primary, Vaira, Valentina, additional, Caino, M. Cecilia, additional, Tang, Hsin-Yao, additional, Seo, Jae Ho, additional, Kossenkov, Andrew V., additional, Ottobrini, Luisa, additional, Martelli, Cristina, additional, Lucignani, Giovanni, additional, Bertolini, Irene, additional, Locatelli, Marco, additional, Bryant, Kelly G., additional, Ghosh, Jagadish C., additional, Lisanti, Sofia, additional, Ku, Bonsu, additional, Bosari, Silvano, additional, Languino, Lucia R., additional, Speicher, David W., additional, and Altieri, Dario C., additional

Published
2016
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183. The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis

Author

Seo, Jae Ho, primary, Rivadeneira, Dayana B., additional, Caino, M. Cecilia, additional, Chae, Young Chan, additional, Speicher, David W., additional, Tang, Hsin-Yao, additional, Vaira, Valentina, additional, Bosari, Silvano, additional, Palleschi, Alessandro, additional, Rampini, Paolo, additional, Kossenkov, Andrew V., additional, Languino, Lucia R., additional, and Altieri, Dario C., additional

Published
2016
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184. Erratum: Corrigendum: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Author

Kaur, Amanpreet, primary, Webster, Marie R., additional, Marchbank, Katie, additional, Behera, Reeti, additional, Ndoye, Abibatou, additional, Kugel, Curtis H., additional, Dang, Vanessa M., additional, Appleton, Jessica, additional, O’Connell, Michael P., additional, Cheng, Phil, additional, Valiga, Alexander A., additional, Morissette, Rachel, additional, McDonnell, Nazli B., additional, Ferrucci, Luigi, additional, Kossenkov, Andrew V., additional, Meeth, Katrina, additional, Tang, Hsin-Yao, additional, Yin, Xiangfan, additional, Wood, William H., additional, Lehrmann, Elin, additional, Becker, Kevin G., additional, Flaherty, Keith T., additional, Frederick, Dennie T., additional, Wargo, Jennifer A., additional, Cooper, Zachary A., additional, Tetzlaff, Michael T., additional, Hudgens, Courtney, additional, Aird, Katherine M., additional, Zhang, Rugang, additional, Xu, Xiaowei, additional, Liu, Qin, additional, Bartlett, Edmund, additional, Karakousis, Giorgos, additional, Eroglu, Zeynep, additional, Lo, Roger S., additional, Chan, Matthew, additional, Menzies, Alexander M., additional, Long, Georgina V., additional, Johnson, Douglas B., additional, Sosman, Jeffrey, additional, Schilling, Bastian, additional, Schadendorf, Dirk, additional, Speicher, David W., additional, Bosenberg, Marcus, additional, Ribas, Antoni, additional, and Weeraratna, Ashani T., additional

Published
2016
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185. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Author

Kaur, Amanpreet, primary, Webster, Marie R., additional, Marchbank, Katie, additional, Behera, Reeti, additional, Ndoye, Abibatou, additional, Kugel, Curtis H., additional, Dang, Vanessa M., additional, Appleton, Jessica, additional, O’Connell, Michael P., additional, Cheng, Phil, additional, Valiga, Alexander A., additional, Morissette, Rachel, additional, McDonnell, Nazli B., additional, Ferrucci, Luigi, additional, Kossenkov, Andrew V., additional, Meeth, Katrina, additional, Tang, Hsin-Yao, additional, Yin, Xiangfan, additional, Wood, William H., additional, Lehrmann, Elin, additional, Becker, Kevin G., additional, Flaherty, Keith T., additional, Frederick, Dennie T., additional, Wargo, Jennifer A., additional, Cooper, Zachary A., additional, Tetzlaff, Michael T., additional, Hudgens, Courtney, additional, Aird, Katherine M., additional, Zhang, Rugang, additional, Xu, Xiaowei, additional, Liu, Qin, additional, Bartlett, Edmund, additional, Karakousis, Giorgos, additional, Eroglu, Zeynep, additional, Lo, Roger S., additional, Chan, Matthew, additional, Menzies, Alexander M., additional, Long, Georgina V., additional, Johnson, Douglas B., additional, Sosman, Jeffrey, additional, Schilling, Bastian, additional, Schadendorf, Dirk, additional, Speicher, David W., additional, Bosenberg, Marcus, additional, Ribas, Antoni, additional, and Weeraratna, Ashani T., additional

Published
2016
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186. NAD+metabolism governs the proinflammatory senescence-associated secretome

Author

Nacarelli, Timothy, Lau, Lena, Fukumoto, Takeshi, Zundell, Joseph, Fatkhutdinov, Nail, Wu, Shuai, Aird, Katherine M., Iwasaki, Osamu, Kossenkov, Andrew V., Schultz, David, Noma, Ken-ichi, Baur, Joseph A., Schug, Zachary, Tang, Hsin-Yao, Speicher, David W., David, Gregory, and Zhang, Rugang

Abstract

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+metabolism influences both tissue ageing and cancer. However, the role of NAD+metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPTexpression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD+signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+augmentation should be administered with precision.

Published
2019
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187. Abstract A04: Aging microenvironment modulates melanoma invasion and metastasis

Author

Kaur, Amanpreet, primary, Marchbank, Katie, additional, Dang, Vanessa, additional, O'Connell, Michael, additional, Webster, Marie, additional, Appleton, Jessica, additional, Cheng, Phil, additional, Valiga, Alexander, additional, Morissette, Rachel, additional, McDonnell, Nazli, additional, Ferrucci, Luigi, additional, Kossenkov, Andrew, additional, Meeth, Katrina, additional, Bosenberg, Marcus, additional, Tang, Hsin-Yao, additional, Yin, Xiangfan, additional, Wood, William, additional, Lehrmann, Elin, additional, Becker, Kevin, additional, Flaherty, Keith, additional, Frederick, Dennie, additional, Wargo, Jennifer, additional, Aird, Katherine, additional, Zhang, Rugang, additional, Xu, Xiaowei, additional, Liu, Qin, additional, Speicher, David, additional, and Weeraratna, Ashani, additional

Published
2015
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192. Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Author

Rasanen, Kati, primary, Sriswasdi, Sira, additional, Valiga, Alexander, additional, Tang, Hsin-Yao, additional, Zhang, Gao, additional, Perego, Michela, additional, Somasundaram, Rajasekharan, additional, Li, Ling, additional, Speicher, Kaye, additional, Klein-Szanto, Andres J., additional, Basu, Devraj, additional, Rustgi, Anil K., additional, Speicher, David W., additional, and Herlyn, Meenhard, additional

Published
2013
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