Chad J Creighton

Baylor College of Medicine, Houston, Texas, United States

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Publications (240)2298.15 Total impact

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    ABSTRACT: Background Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. Results Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). Conclusions Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
    New England Journal of Medicine 11/2015; DOI:10.1056/NEJMoa1505917 · 55.87 Impact Factor
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    ABSTRACT: The cancer stem-like cells (CSLCs) are tumorigenic cells promoting initiation, progression, and spread of the tumor. Accumulating evidences suggested the presence of CSLCs in distinct tumors including laryngeal squamous cell carcinoma (LSCC). MicroRNAs have been proposed as significant regulators of carcinogenesis, and several of them have been demonstrated to have direct roles in survival of CSLCs. In this study, we aimed to explore the role of miR-145, which is downregulated in LSCC, on cancer stem cell potency of laryngeal cancer cells. We initially showed the downregulation of miR-145 expression in tumor tissue samples and in CD133-enriched CSLCs. Quantitative reverse-transcription PCR (qRT-PCR) analysis of miR-145-transfected Hep-2 cells demonstrated the inhibitory role of miR-145 on stem cell markers like SOX2, OCT4, KLF4, and ABCG2. We, then, investigated the stem cell features of miR-145-overexpressing Hep-2 cells by sphere formation assay, single-cell cloning assay, and aldehyde dehydrogenase (ALDH) assay, which all demonstrated the inhibition of stem cell potency upon miR-145 overexpression. Further qRT-PCR analysis demonstrated altered expression of epithelial to mesenchymal transition markers in miR-145-overexpressing Hep-2 cells. In conclusion, we demonstrated the regulatory role of miR-145 in stem cell characteristics of Hep-2 cells. Based on these results, we propose that miR-145 might carry crucial roles in LSCC tumorigenesis, prognosis, metastasis, chemoresistance, and recurrence through regulating stem cell properties of tumor cells.
    Tumor Biology 10/2015; DOI:10.1007/s13277-015-4219-z · 3.61 Impact Factor
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    ABSTRACT: Purpose: Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a "hallmark" of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the p53-MDM2 axis as a potential therapeutic target for DDLPS. Here we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models. Experimental design: The therapeutic effectiveness of SAR405838 was compared to the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched. Results: SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment. Conclusion: SAR405838 is currently in early phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-1522 · 8.72 Impact Factor
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    J. Kim · R. Akbani · C. J. Creighton · S. P. Lerner · J. N. Weinstein · G. Getz · D. J. Kwiatkowski ·

    Clinical Cancer Research 10/2015; 21(20):4514-4524. DOI:10.1158/1078-0432.CCR-14-1215 · 8.72 Impact Factor
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    ABSTRACT: Implications: The current study suggests a clinical role for HDACi in human ES, Which when combined with EZH2 inhibitors could serve as a novel therapeutic strategy for ES patients. Future investigations targeting specific HDAC isoforms along with EZH2 may potentially maximizing treatment efficacy.
    Molecular Cancer Research 09/2015; DOI:10.1158/1541-7786.MCR-15-0295 · 4.38 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen species and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases the expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in the hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Last, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for the treatment of dilated cardiomyopathy.
    Nature Communications 09/2015; 6:8245. DOI:10.1038/ncomms9245 · 11.47 Impact Factor
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    ABSTRACT: BACKGROUND Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment.METHODS The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis.RESULTSThe results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin.CONCLUSION Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment. Cancer 2015. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
    Cancer 09/2015; DOI:10.1002/cncr.29564 · 4.89 Impact Factor
  • Paul T Fullerton · Chad J Creighton · Martin M Matzuk ·
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer death in the United States. The transforming growth factor β (TGF-β) signaling protein SMAD4 is lost in 60 of PDAC, and this has been associated with poorer prognosis. However, the mechanisms by which SMAD4 loss promotes PDAC development are not fully understood. We expressed SMAD4 in human PDAC cell lines BxPC3 and CFPAC1 by selection of stable clones containing an inducible SMAD4 Tet-ON construct. After 24h of SMAD4 expression, TGF-β signaling-dependent G1-arrest was observed in BxPC3 cells with an increase in the G1-phase fraction from 48.9% to 71.5%. Inhibition of CDKN1A by siRNA eliminated the anti-proliferative effect, indicating that upregulation of CDKN1A/p21 by TGF-β signaling is necessary for the phenotype. SMAD4 expression had no impact on invasion in BxPC3 cells, but reduced migration. Microarray analysis of gene expression at 8h, 24h, and 48h after SMAD4 expression characterized the regulatory impact of SMAD4 expression in a SMAD4-null PDAC cell line and identified novel targets of TGF-β signaling. Among the novel TGF-β targets identified are anthrax toxin receptor 2 (ANTXR2; 3.58x at 8h), tubulin, beta 3 class III (TUBB3; 7.35x at 8h), cell migration inducing protein, hyaluronan binding (KIAA1199; 8.07x at 8h), interleukin 1 receptor-like 1 (IL1RL1; 0.403x at 8h), regulator of G-protein signaling 4 (RGS4; 0.293x at 8h), and THAP domain containing 11 (THAP11; 0.262x at 8h). The gene expression changes we observed upon restoration of TGF-β signaling provide numerous new targets for future investigations into PDAC biology and progression.
    Molecular Endocrinology 08/2015; 29(10):me20151102. DOI:10.1210/me.2015-1102 · 4.02 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3055-3055. DOI:10.1158/1538-7445.AM2015-3055 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):1078-1078. DOI:10.1158/1538-7445.AM2015-1078 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2969-2969. DOI:10.1158/1538-7445.AM2015-2969 · 9.33 Impact Factor
  • Jian Liu · Sung-Nam Cho · Yiqun Zhang · Chad J. Creighton · Francesco J. DeMayo ·

    Cancer Research 08/2015; 75(15 Supplement):2308-2308. DOI:10.1158/1538-7445.AM2015-2308 · 9.33 Impact Factor

  • Cancer Research; 08/2015

  • Cancer Research 08/2015; 75(15 Supplement):1099-1099. DOI:10.1158/1538-7445.AM2015-1099 · 9.33 Impact Factor
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    ABSTRACT: POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related with the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed to identify the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of Whole Exome Sequencing (WES).A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed gene expression array and compared their expression profiles to that of control fibroblast cells. Gene Expression Array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A was accompanied by alterations in another centrosome associated WD repeat protein p80-katanin.As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 07/2015; 24(19). DOI:10.1093/hmg/ddv261 · 6.39 Impact Factor
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    ABSTRACT: Basal-like breast cancers (BLBCs) are aggressive, and their drivers are unclear. We have found that wild-type N-RAS is overexpressed in BLBCs but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, whereas overexpression enhances these processes even in preinvasive BLBC cells. We identified N-Ras-responsive genes, most of which encode chemokines; e.g., IL8. Expression levels of these chemokines and N-RAS in tumors correlate with outcome. N-Ras, but not K-Ras, induces IL-8 by binding and activating the cytoplasmic pool of JAK2; IL-8 then acts on both the cancer cells and stromal fibroblasts. Thus, BLBC progression is promoted by increasing activities of wild-type N-Ras, which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(3). DOI:10.1016/j.celrep.2015.06.044 · 8.36 Impact Factor
  • Shixia Huang · Chad J Creighton ·
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    ABSTRACT: The reverse phase protein array (RPPA) data platform provides expression data for a prespecified set of proteins, across a set of tissue or cell line samples. Being able to measure either total proteins or posttranslationally modified proteins, even ones present at lower abundances, RPPA represents an excellent way to capture the state of key signaling transduction pathways in normal or diseased cells. RPPA data can be combined with those of other molecular profiling platforms, in order to obtain a more complete molecular picture of the cell. This review offers perspective on the use of RPPA as a component of integrative molecular analysis, using recent case examples from The Cancer Genome Altas consortium, showing how RPPA may provide additional insight into cancer besides what other data platforms may provide. There also exists a clear need for effective visualization approaches to RPPA-based proteomic results; this was highlighted by the recent challenge, put forth by the HPN-DREAM consortium, to develop visualization methods for a highly complex RPPA dataset involving many cancer cell lines, stimuli, and inhibitors applied over time course. In this review, we put forth a number of general guidelines for effective visualization of complex molecular datasets, namely, showing the data, ordering data elements deliberately, enabling generalization, focusing on relevant specifics, and putting things into context. We give examples of how these principles can be utilized in visualizing the intrinsic subtypes of breast cancer and in meaningfully displaying the entire HPN-DREAM RPPA dataset within a single page.
    Drug Design, Development and Therapy 07/2015; 9:3519. DOI:10.2147/DDDT.S38375 · 3.03 Impact Factor
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    ABSTRACT: Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.Modern Pathology advance online publication, 26 June 2015; doi:10.1038/modpathol.2015.68.
    Modern Pathology 06/2015; 28(9). DOI:10.1038/modpathol.2015.68 · 6.19 Impact Factor
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    06/2015; 1(1). DOI:10.1016/j.euf.2014.11.002
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    Shu Feng · Jianghua Wang · Yiqun Zhang · Chad J Creighton · Michael Ittmann ·
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    ABSTRACT: Prostate cancer is the most common cancer in US men and the second leading cause of cancer deaths. Fibroblast growth factor 23 (FGF23) is an endocrine FGF, normally expressed by osteocytes, which plays a critical role in phosphate homeostasis via a feedback loop involving the kidney and vitamin D. We now show that FGF23 is expressed as an autocrine growth factor in all prostate cancer cell lines tested and is present at increased levels in prostate cancer tissues. Exogenous FGF23 enhances proliferation, invasion and anchorage independent growth in vitro while FGF23 knockdown in prostate cancer cell lines decreases these phenotypes. FGF23 knockdown also decreases tumor growth in vivo. Given that classical FGFs and FGF19 are also increased in prostate cancer, we analyzed expression microarrays hybridized with RNAs from of LNCaP cells stimulated with FGF2, FGF19 or FGF23. The different FGF ligands induce overlapping as well as unique patterns of gene expression changes and thus are not redundant. We identified multiple genes whose expression is altered by FGF23 that are associated with prostate cancer initiation and progression. Thus FGF23 can potentially also act as an autocrine, paracrine and/or endocrine growth factor in prostate cancer that can promote prostate cancer progression.
    Oncotarget 05/2015; 6(19). DOI:10.18632/oncotarget.4174 · 6.36 Impact Factor

Publication Stats

11k Citations
2,298.15 Total Impact Points


  • 2007-2015
    • Baylor College of Medicine
      • • Department of Pediatrics
      • • Dan L. Duncan Cancer Center
      • • Department of Molecular & Cellular Biology
      • • Department of Medicine
      Houston, Texas, United States
  • 2012
    • Memorial Sloan-Kettering Cancer Center
      • Division of Computational Biology
      New York, New York, United States
  • 2011
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2010
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 2009
    • Texas Children's Cancer and Hematology Centers
      Houston, Texas, United States
  • 2008
    • University of Texas MD Anderson Cancer Center
      • Department of Thoracic Head Neck Medical Oncology
      Houston, TX, United States
  • 2006-2007
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2003-2006
    • University of Michigan
      • • Department of Internal Medicine
      • • Department of Human Genetics
      Ann Arbor, Michigan, United States
  • 2005
    • Michigan Institute of Urology
      Detroit, Michigan, United States