Biological Phenomena, Cell Phenomena, and Immunity | Open Access Articles

Generation And Validation Of An Anti-Human Pank3 Mouse Monoclonal Antibody, Sunada Khadka, Long Vien, Paul Leonard, Laura Bover, Florian Muller

Faculty, Staff and Student Publications

Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step-phosphorylation of pantothenic acid-catalyzed by pantothenate kinases (PANK1,2,3 in humans, PANK3 being the most highly expressed). Despite the critical importance of CoA in metabolism, the differential roles of PANK isoforms remain poorly understood. Our investigations of PANK proteins as potential precision oncology collateral lethality targets (PANK1 is co-deleted as part of the PTEN locus in some highly aggressive cancers) were severely hindered by a dearth of commercial antibodies that can reliably detect endogenous PANK3 protein. While …

Go to article

Structural Plasticity Can Produce Metaplasticity, Wenli Zhao, Shuo Han, Na Qiu, Wenbo Feng, Mengjie Lu, Wenru Zhang, Mu Wang, Qingtong Zhou, Shutian Chen, Wei Xu, Juan Du, Xiaojing Chu, Cuiying Yi, Antao Dai, Liaoyuan Hu, Michelle Y Shen, Yaping Sun, Qing Zhang, Yingli Ma, Wenge Zhong, Dehua Yang, Ming-Wei Wang, Beili Wu, Qiang Zhao

Faculty, Staff and Student Publications

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the …

Go to article

Targeting Syndecan-1: New Opportunities In Cancer Therapy, Zecheng Yang, Shuaitong Chen, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles …

Go to article

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Go to article

Invariant Natural Killer T-Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing And Antitumor Effects, Kristina Maas-Bauer, Juliane K Lohmeyer, Toshihito Hirai, Teresa Lopes Ramos, Furqan M Fazal, Ulrike M Litzenburger, Kathryn E Yost, Jessica V Ribado, Neeraja Kambham, Arielle S Wenokur, Po-Yu Lin, Maite Alvarez, Melissa Mavers, Jeanette Baker, Ami S Bhatt, Howard Y Chang, Federico Simonetta, Robert S Negrin

Faculty, Staff and Students Publications

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, …

Go to article

Characterization Of Malt1 Inhibitors And Their Effect On Leukemic Cell Growth Properties, Christina Snyder

Graduate School of Biomedical Sciences Theses and Dissertations

Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions …

Go to article

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

Department of Cancer Biology Faculty Papers

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.

Go to article

Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Full-Text Articles in Biological Phenomena, Cell Phenomena, and Immunity

Generation And Validation Of An Anti-Human Pank3 Mouse Monoclonal Antibody, Sunada Khadka, Long Vien, Paul Leonard, Laura Bover, Florian Muller

Faculty, Staff and Student Publications

Faculty, Staff and Student Publications

Targeting Syndecan-1: New Opportunities In Cancer Therapy, Zecheng Yang, Shuaitong Chen, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Faculty, Staff and Student Publications

Faculty, Staff and Students Publications

Characterization Of Malt1 Inhibitors And Their Effect On Leukemic Cell Growth Properties, Christina Snyder

Graduate School of Biomedical Sciences Theses and Dissertations

Department of Cancer Biology Faculty Papers