Cancer Cell (CANCER CELL)

Publications in this journal

• Article: Modeling Clear Cell Sarcomagenesis in the Mouse: Cell of Origin Differentiation State Impacts Tumor Characteristics

  Krystal M. Straessler, Kevin B. Jones, Hao Hu, Huifeng Jin, Matt van de Rijn, Mario R. Capecchi
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  ABSTRACT: Clear cell sarcoma (CCS) of tendons and aponeuroses is a deadly soft-tissue malignancy resembling melanoma, with a predilection for young adults. EWS-ATF1, the fusion product of a balanced chromosomal translocation between chromosomes 22 and 12, is considered the definitional feature of the tumor. Conditional expression of the EWS-ATF1 human cDNA in the mouse generates CCS-like tumors with 100% penetrance. Tumors, developed through varied means of initiating expression of the fusion oncogene, model human CCS morphologically, immunohistochemically, and by genome-wide expression profiling. We also demonstrate that although fusion oncogene expression in later stages of differentiation can transform mesenchymal progenitor cells and generate tumors resembling CCS generally, expression in cells retaining stem cell markers permits the full melanoma-related phenotype.
  Cancer Cell 02/2013;
• Article: Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells

  Josep Domingo-Domenech, Samuel J. Vidal, Veronica Rodriguez-Bravo, Mireia Castillo-Martin, S. Aidan Quinn, Ruth Rodriguez-Barrueco, Dennis M. Bonal, Elizabeth Charytonowicz, Nataliya Gladoun, Janis de la Iglesia-Vicente, Daniel P. Petrylak, Mitchell C. Benson, Jose M. Silva, Carlos Cordon-Cardo
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  ABSTRACT: Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prog- nosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemo- therapy resistance and tumor progression.
  Cancer Cell 09/2012; 22:373.
• Article: LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma.

  Liu W, Monahan KB, Pfefferle AD, Shimamura T, Sorrentino J, Chan KT, Roadcap DW, Ollila DW, Thomas NE, Castrillon DH, Miller CR, Perou CM, Wong KK, Bear JE, Sharpless NE
  Cancer Cell 06/2012;
• Article: Targeting Nonclassical Oncogenes for Therapy in T-ALL

  Prem S. Subramaniam, Dosh W. Whye, Evgeni Efimenko, Jianchung Chen, Valeria Tosello, Kim De Keersmaecker, Adam Kashishian, Mary Ann Thompson, Mireia Castillo, Carlos Cordon-Cardo, Utpal P. Davé, Adolfo Ferrando, Brian J. Lannutti, Thomas G. Diacovo
  Cancer Cell 04/2012; 21(4):459–472.
• Article: The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors

  Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, [......], Chen H, Morosini D, Bell K, Alimzhanov M, Ioannidis S, McCoon P, Cao ZA, Yu H, Jove R, Zinda M
  Cancer Cell 12/2009;
• Article: Cancer Cell. 2008 Nov 4;14(5):369-81.NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma.Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, Cheng A, Hall BM, Qualman SJ, Chandler DS, Croce CM, Guttridge DC.

  Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, Cheng A, Hall BM, Qualman SJ, Chandler DS, Croce CM, Guttridge DC
  Cancer Cell 11/2008;
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  Available from: georgiahealth.edu

  Article: Significance of CD90+ cancer stem cells in human liver cancer.

  Zhen Fan Yang, David W Ho, Michael N Ng, Chi Keung Lau, Wan Ching Yu, Patricia Ngai, Patrick W K Chu, Chi Tat Lam, Ronnie T P Poon, Sheung Tat Fan
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  ABSTRACT: This study characterized cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) cell lines, tumor specimens, and blood samples. The CD90+ cells, but not the CD90(-) cells, from HCC cell lines displayed tumorigenic capacity. All the tumor specimens and 91.6% of blood samples from liver cancer patients bore the CD45(-)CD90+ population, which could generate tumor nodules in immunodeficient mice. The CD90+CD44+ cells demonstrated a more aggressive phenotype than the CD90+CD44(-) counterpart and formed metastatic lesions in the lung of immunodeficient mice. CD44 blockade prevented the formation of local and metastatic tumor nodules by the CD90+ cells. Differential gene expression profiles were identified in the CD45(-)CD90+ and CD45(-)CD90(-) cells isolated from tissue and blood samples from liver cancer patients and controls.
  Cancer Cell 03/2008; 13(2):153-66.
• Article: The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.

  Nancy M Joseph, Jack T Mosher, Johanna Buchstaller, Paige Snider, Paul E McKeever, Megan Lim, Simon J Conway, Luis F Parada, Yuan Zhu, Sean J Morrison
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  ABSTRACT: Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.
  Cancer Cell 03/2008; 13(2):129-40.
• Article: GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.

  Hosein Kouros-Mehr, Seth K Bechis, Euan M Slorach, Laurie E Littlepage, Mikala Egeblad, Andrew J Ewald, Sung-Yun Pai, I-Cheng Ho, Zena Werb
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  ABSTRACT: How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted deletion of GATA-3 in early tumors led to apoptosis of differentiated cells, indicating that its loss is not sufficient for malignant conversion. Rather, malignant progression occurred with an expanding GATA-3-negative tumor cell population. These data indicate that GATA-3 regulates tumor differentiation and suppresses tumor dissemination in breast cancer.
  Cancer Cell 03/2008; 13(2):141-52.
• Article: Deathproof: new insights on the role of skp2 in tumorigenesis.

  Steven I Reed
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  ABSTRACT: The F box protein Skp2 is frequently overexpressed in human tumors and is capable of transforming cultured cells in vitro. It has been assumed, quite reasonably, that this oncogenic property of Skp2 is directly related to its role, as part of an SCF ubiquitin ligase complex, in the ubiquitin-mediated proteolysis of negative cell cycle regulatory proteins, notably p27Kip1. However, building on earlier results indicating that silencing of Skp2 promotes apoptosis in some tumor-derived cell lines, Kitagawa and coworkers in the February 1 issue of Molecular Cell have elucidated an alternative mechanism for promotion of tumorigenesis by Skp2, specifically the suppression of p53-mediated apoptosis.
  Cancer Cell 03/2008; 13(2):88-9.
• Article: Unraveling the complexity of endocrine resistance in breast cancer by functional genomics.

  Charles Swanton, Julian Downward
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  ABSTRACT: Despite the proven benefit of antiestrogen drugs in breast cancer treatment, resistant disease ultimately develops in advanced breast cancer. In this issue of Cancer Cell, Iorns et al. find that loss of CDK10 expression promotes resistance of cells to tamoxifen and is associated with poor outcome in breast cancer patients treated with the drug. CDK10 loss increases the activity of the transcription factor ETS2 on the promoter of the RAF1 gene, elevating ERK/MAPK kinase pathway activity and relieving tamoxifen-induced G1 arrest. CDK10 is thus a potential biomarker for sensitivity in prospective clinical trials of patients treated with endocrine therapies.
  Cancer Cell 03/2008; 13(2):83-5.
• Article: AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies.

  Marta Chesi, Davide F Robbiani, Michael Sebag, Wee Joo Chng, Maurizio Affer, Rodger Tiedemann, Riccardo Valdez, Stephen E Palmer, Stephanie S Haas, A Keith Stewart, Rafael Fonseca, Richard Kremer, Giorgio Cattoretti, P Leif Bergsagel
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  ABSTRACT: By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B cells of Vk*MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma.
  Cancer Cell 03/2008; 13(2):167-80.
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  Article: Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer.

  Elizabeth Iorns, Nicholas C Turner, Richard Elliott, Nelofer Syed, Ornella Garrone, Milena Gasco, Andrew N J Tutt, Tim Crook, Christopher J Lord, Alan Ashworth
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  ABSTRACT: Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.
  Cancer Cell 03/2008; 13(2):91-104.
• Article: Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation.

  Huarui Zheng, Lou Chang, Neha Patel, Jiong Yang, Lori Lowe, Dennis K Burns, Yuan Zhu
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  ABSTRACT: Recent evidence suggests that alterations in the self-renewal program of stem/progenitor cells can cause tumorigenesis. By utilizing genetically engineered mouse models of neurofibromatosis type 1 (NF1), we demonstrated that plexiform neurofibroma, the only benign peripheral nerve sheath tumor with potential for malignant transformation, results from Nf1 deficiency in fetal stem/progenitor cells of peripheral nerves. Surprisingly, this did not cause hyperproliferation or tumorigenesis in early postnatal period. Instead, peripheral nerve development appeared largely normal in the absence of Nf1 except for abnormal Remak bundles, the nonmyelinated axon-Schwann cell unit, identified in postnatal mutant nerves. Subsequent degeneration of abnormal Remak bundles was accompanied by initial expansion of nonmyelinating Schwann cells. We suggest abnormally differentiated Remak bundles as a cell of origin for plexiform neurofibroma.
  Cancer Cell 03/2008; 13(2):117-28.
• Article: Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells.

  Jianqiang Wu, Jon P Williams, Tilat A Rizvi, Jennifer J Kordich, David Witte, Dies Meijer, Anat O Stemmer-Rachamimov, Jose A Cancelas, Nancy Ratner
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  ABSTRACT: Neurofibromatosis type 1 (Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5 + 1, but not earlier (neural crest) or later (mature Schwann cell), results in colony-forming cells capable of multilineage differentiation. In vivo, inactivation of Nf1 using a DhhCre driver beginning at E12.5 elicits plexiform neurofibromas, dermal neurofibromas, and pigmentation. Tumor Schwann cells uniquely show biallelic Nf1 inactivation. Peripheral nerve and tumors contain transiently proliferating Schwann cells that lose axonal contact, providing insight into early neurofibroma formation. We suggest that timing of Nf1 mutation is critical for neurofibroma formation.
  Cancer Cell 03/2008; 13(2):105-16.