Cancer cell

Publications in this journal

• Article: Gain of Interaction with IRS1 by p110α-Helical Domain Mutants Is Crucial for Their Oncogenic Functions.

  Yujun Hao, Chao Wang, Bo Cao, Brett M Hirsch, Jing Song, Sanford D Markowitz, Rob M Ewing, David Sedwick, Lili Liu, Weiping Zheng, Zhenghe Wang
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  ABSTRACT: PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots: E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110α E545K, but not p110α H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K.
  Cancer cell 04/2013;
• Article: Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP.

  Min Lu, Hilde Breyssens, Victoria Salter, Shan Zhong, Ying Hu, Caroline Baer, Indrika Ratnayaka, Alex Sullivan, Nicholas R Brown, Jane Endicott, [......], Benedikt M Kessler, Mark R Middleton, Christian Siebold, E Yvonne Jones, Elena V Sviderskaya, Jonathan Cebon, Thomas John, Otavia L Caballero, Colin R Goding, Xin Lu
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  ABSTRACT: Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.
  Cancer cell 04/2013;
• Article: A NIK-IKKα Module Expands ErbB2-Induced Tumor-Initiating Cells by Stimulating Nuclear Export of p27/Kip1.

  Weizhou Zhang, Wei Tan, Xuefeng Wu, Maxim Poustovoitov, Amy Strasner, Wei Li, Nicholas Borcherding, Majid Ghassemian, Michael Karin
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  ABSTRACT: IκB kinase α (IKKα) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKKα and its activator, NF-κB-inducing kinase (NIK), support the expansion of tumor-initiating cells (TICs) that copurify with a CD24(med)CD49f(hi) population from premalignant ErbB2-expressing mammary glands. Upon activation, IKKα enters the nucleus, phosphorylates the cyclin-dependent kinase (CDK) inhibitor p27/Kip1, and stimulates its nuclear export or exclusion. Reduced p27 expression rescues mammary tumorigenesis in mice deficient in IKKα kinase activity and restores TIC self-renewal. IKKα is also likely to be involved in human breast cancer, where its expression shows an inverse correlation with metastasis-free survival, and its presence in the nucleus of invasive ductal carcinomas (IDCs) is associated with decreased nuclear p27 abundance.
  Cancer cell 04/2013;
• Article: 1B50-1, a mAb Raised against Recurrent Tumor Cells, Targets Liver Tumor-Initiating Cells by Binding to the Calcium Channel α2δ1 Subunit.

  Wei Zhao, Limin Wang, Haibo Han, Kemin Jin, Na Lin, Ting Guo, Yangde Chen, Heping Cheng, Fengmin Lu, Weigang Fang, Yu Wang, Baocai Xing, Zhiqian Zhang
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  ABSTRACT: The identification and targeted therapy of cells involved in hepatocellular carcinoma (HCC) recurrence remain challenging. Here, we generated a monoclonal antibody against recurrent HCC, 1B50-1, that bound the isoform 5 of the α2δ1 subunit of voltage-gated calcium channels and identified a subset of tumor-initiating cells (TICs) with stem cell-like properties. A surgical margin with cells detected by 1B50-1 predicted rapid recurrence. Furthermore, 1B50-1 had a therapeutic effect on HCC engraftments by eliminating TICs. Finally, α2δ1 knockdown reduced self-renewal and tumor formation capacities and induced apoptosis of TICs, whereas its overexpression led to enhanced sphere formation, which is regulated by calcium influx. Thus, α2δ1 is a functional liver TIC marker, and its inhibitors may serve as potential anti-HCC drugs.
  Cancer cell 04/2013; 23(4):541-556.
• Article: Sirt4: The Glutamine Gatekeeper.

  Pablo J Fernandez-Marcos, Manuel Serrano
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  ABSTRACT: Little is known about how DNA damage and metabolism are interconnected. In this issue of Cancer Cell, Jeong and colleagues report that an important component of the DNA damage response is the SIRT4-mediated blockade of glutamine catabolism. Failure to shut down glutamine consumption results in unscheduled proliferation, genomic instability, and cancer.
  Cancer cell 04/2013; 23(4):427-428.
• Article: A Human ICAM-1 Antibody Isolated by a Function-First Approach Has Potent Macrophage-Dependent Antimyeloma Activity In Vivo.

  Niina Veitonmäki, Markus Hansson, Fenghuang Zhan, Annika Sundberg, Tobias Löfstedt, Anne Ljungars, Zhan-Chun Li, Titti Martinsson-Niskanen, Ming Zeng, Ye Yang, Lena Danielsson, Mathilda Kovacek, Andrea Lundqvist, Linda Mårtensson, Ingrid Teige, Guido Tricot, Björn Frendéus
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  ABSTRACT: We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.
  Cancer cell 04/2013; 23(4):502-515.
• Article: Autophagy in Multiple Myeloma: What Makes You Stronger Can Also Kill You.

  Richard G Carroll, Seamus J Martin
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  ABSTRACT: Autophagy, a process for recycling cellular constituents, is normally associated with cell survival and is thought to be beneficial for tumor maintenance. However, in this issue of Cancer Cell, Lamy and colleagues report that multiple myeloma utilizes caspase-10 to restrain autophagy and undergoes autophagic cell death upon its removal or inhibition.
  Cancer cell 04/2013; 23(4):425-426.
• Article: It's the Peptide-MHC Affinity, Stupid.

  Thomas Kammertoens, Thomas Blankenstein
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  ABSTRACT: Adoptively transferred T cells can reject large established tumors, but recurrence due to escape variants frequently occurs. In this issue of Cancer Cell, Engels et al. demonstrate that the affinity of the target peptide to the MHC molecule determines whether large tumors will relapse following adoptive T cell therapy.
  Cancer cell 04/2013; 23(4):429-431.
• Article: The Pivotal Role of IKKα in the Development of Spontaneous Lung Squamous Cell Carcinomas.

  Zuoxiang Xiao, Qun Jiang, Jami Willette-Brown, Sichuan Xi, Feng Zhu, Sandra Burkett, Timothy Back, Na-Young Song, Mahesh Datla, Zhonghe Sun, [......], Fanching Lin, Travis Cohoon, Kristen Pike, Xiaolin Wu, David S Schrump, Kwok-Kin Wong, Howard A Young, Giorgio Trinchieri, Robert H Wiltrout, Yinling Hu
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  ABSTRACT: Here, we report that kinase-dead IKKα knockin mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKα(low)K5(+)p63(hi) cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with wild-type bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα mutant macrophages promote the transition of IKKα(low)K5(+)p63(hi) cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.
  Cancer cell 04/2013; 23(4):527-540.
• Article: SIRT4 Has Tumor-Suppressive Activity and Regulates the Cellular Metabolic Response to DNA Damage by Inhibiting Mitochondrial Glutamine Metabolism.

  Seung Min Jeong, Cuiying Xiao, Lydia W S Finley, Tyler Lahusen, Amanda L Souza, Kerry Pierce, Ying-Hua Li, Xiaoxu Wang, Gaëlle Laurent, Natalie J German, [......], Cuiling Li, Rui-Hong Wang, Jaewon Lee, Alfredo Csibi, Richard Cerione, John Blenis, Clary B Clish, Alec Kimmelman, Chu-Xia Deng, Marcia C Haigis
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  ABSTRACT: DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.
  Cancer cell 04/2013;
• Article: Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma.

  Laurence Lamy, Vu N Ngo, N C Tolga Emre, Arthur L Shaffer, Yandan Yang, Erming Tian, Vinod Nair, Michael J Kruhlak, Adriana Zingone, Ola Landgren, Louis M Staudt
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  ABSTRACT: We performed a loss-of-function RNA interference screen to define therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.
  Cancer cell 03/2013;
• Article: Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer.

  Di Zhao, Shao-Wu Zou, Ying Liu, Xin Zhou, Yan Mo, Ping Wang, Yan-Hui Xu, Bo Dong, Yue Xiong, Qun-Ying Lei, Kun-Liang Guan
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  ABSTRACT: Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1α may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.
  Cancer cell 03/2013;
• Article: Ablation of fbxw7 eliminates leukemia-initiating cells by preventing quiescence.

  Shoichiro Takeishi, Akinobu Matsumoto, Ichiro Onoyama, Kazuhito Naka, Atsushi Hirao, Keiichi I Nakayama
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  ABSTRACT: Imatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML.
  Cancer cell 03/2013; 23(3):347-61.
• Article: SnapShot: Pancreatic Cancer.

  Haiyong Han, Daniel D Von Hoff
  Cancer cell 03/2013; 23(3):424-424.e1.
• Article: Tumor Dissemination: An EMT Affair.

  Jean Paul Thiery, Chwee Teck Lim
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  ABSTRACT: A recent paper reports that circulating tumor cells (CTCs) from metastatic breast cancer patients exhibit heterogeneous epithelial and mesenchymal phenotypes and that CTCs display higher frequencies of partial or full-blown mesenchymal phenotype than carcinoma cells within primary tumors. Mesenchymal-like CTCs are also elevated in patients who are refractory to therapy.
  Cancer cell 03/2013; 23(3):272-3.
• Article: R-2-Hydroxyglutarate as the Key Effector of IDH Mutations Promoting Oncogenesis.

  Dan Ye, Shenghong Ma, Yue Xiong, Kun-Liang Guan
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  ABSTRACT: The tumor-associated isocitrate dehydrogenase (IDH) mutants are unique in that they have lost their normal catalytic activity and gained a novel function to produce R-2-hydroxyglutarate (R-2-HG). A recent study now shows that R-2-HG can reversibly promote leukemogenesis in vitro, suggesting a therapeutic potential of targeting mutant IDH1 and IDH2.
  Cancer cell 03/2013; 23(3):274-6.