Timothy J Yeatman

Gibbs Cancer Center, SPA, South Carolina, United States

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Publications (196)1170.43 Total impact

  • Bernard Omolo · Barbara Centeno · Timothy Yeatman
    Cancer Research 08/2015; 75(15 Supplement):2186-2186. DOI:10.1158/1538-7445.AM2015-2186 · 9.33 Impact Factor
  • Mingli Yang · Michael J. Schell · Norman H. Lee · Timothy J. Yeatman
    Cancer Research 08/2015; 75(15 Supplement):2981-2981. DOI:10.1158/1538-7445.AM2015-2981 · 9.33 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil (5-FU) are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excess MCM complexes function as back-up initiation sites under conditions of replicative stress. The current study provides definitive evidence that co-suppression of the excess/back-up MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared to drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are non-tumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when co-suppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. These studies demonstrate that suppressing the back-up complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Research 06/2015; 13(9). DOI:10.1158/1541-7786.MCR-14-0464 · 4.38 Impact Factor
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    ABSTRACT: Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS) to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens. 468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic) specimens. An average of 33.3 mutations/tumor were concordant (shared) between matched samples, including common well-known genes (APC, KRAS, TP53). An average of 2.3 mutations/tumor were discordant (unshared) among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7%)) paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs), ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs), SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair). Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-naïve patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution.
    PLoS ONE 05/2015; 10(5):e0126670. DOI:10.1371/journal.pone.0126670 · 3.23 Impact Factor
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    ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10). This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.
    PLoS ONE 01/2015; 10(1):e0116869. DOI:10.1371/journal.pone.0116869 · 3.23 Impact Factor
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    ABSTRACT: Background: Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC. Patients and methods: Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression. Results: From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34-92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant. Conclusions: Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.
    Acta oncologica (Stockholm, Sweden) 12/2014; 54(4):1-6. DOI:10.3109/0284186X.2014.990158 · 3.00 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-188-LB-188. DOI:10.1158/1538-7445.AM2014-LB-188 · 9.33 Impact Factor
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    ABSTRACT: Background: Senescence-associated genes (SAGs) are responsible for the senescence-associated secretory phenotype, linked in turn to cellular aging, the aging brain, and the pathogenesis of cancer. Objective: We hypothesized that senescence-associated genes are overexpressed in older patients, in higher grades of glioma, and portend a poor prognosis. Methods: Forty-seven gliomas were arrayed on a custom version of the Affymetrix HG-U133 + 2.0 GeneChip, for expression of fo(u)rteen senescence-associated genes: CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM-1, IGFBP-3, IL-6, IL-8, SAA4, TNFRSF-11B, TNFSF-11 and TP53. A combined "senescence score" was generated using principal component analysis to measure the combined effect of the senescence-associated gene signature. Results: An elevated senescence score correlated with older age (r = 0.37; P = .01) as well as a higher degree of malignancy, as determined by WHO, histological grade (r = 0.49; P < .001). There was a mild association with poor prognosis (P = .06). Gliosarcomas showed the highest scores. Six genes independently correlated with either age (IL-6, TNFRSF-11B, IGFBP-3, SAA4, and COPG), prognosis (IL-6, SAA4), or the grade of the glioma (IL-6, IL-8, ICAM-1, IGFBP-3, and COPG). Conclusion: We report: 1) a novel molecular signature in human gliomas, based on cellular senescence, translating the concept of SAG to human cancer, 2) the senescence signature is composed of genes central to the pathogenesis of gliomas, defining a novel, aggressive subtype of glioma; and 3) these genes provide prognostic biomarkers, as well as targets, for drug discovery and immunotherapy.
    Journal of Geriatric Oncology 09/2014; 5(4). DOI:10.1016/j.jgo.2014.08.003 · 1.86 Impact Factor
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    ABSTRACT: Aims Based on KRAS testing, the subset of patients with metastatic colorectal cancer (CRC) that could benefit from anti-EGFR therapy can be better delineated. Though KRAS testing has become significantly more prevalent over the last few years, methods for testing remain heterogeneous and discordance has been reported between methods. Methods In this study, we examined a CRC patient population and compared KRAS testing done in Clinical Laboratory Improvement Amendments (CLIA) approved laboratories as part of standard clinical care and by next-generation sequencing (NGS) using the Illumina platform. Discordances were further evaluated with manual review of the NGS testing. Results Out of 468 CRC patient samples, 77 had KRAS testing done by both CLIA assay and NGS. There were concordant results between testing methodologies in 74 out of 77 patients, or 96% (95% CI 89% to 99%). There were three patient samples that showed discordant results between the two methods of testing. Upon further investigation of the NGS results for the three discordant cases, one sample showed a low level of the mutation seen in the standard testing, one sample showed low tumour fraction and a third did not show any evidence of the mutation that was found with the standard assay. Five patients had KRAS mutations not typically tested with standard testing. Conclusions Overall there was a high concordance rate between NGS and standard testing for KRAS. However, NGS revealed mutations that are not tested for with standard KRAS assays that might have clinical impact with regards to the role for anti-EGFR therapy.
    Journal of Clinical Pathology 07/2014; 67(9). DOI:10.1136/jclinpath-2014-202405 · 2.92 Impact Factor
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    Chang Gong Lee · Susan McCarthy · Mike Gruidl · Cindy Timme · Timothy J Yeatman
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    ABSTRACT: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy. An analysis of patients (n = 71) profiled with both gene expression and a global microRNA assessment (∼415 miRs) identified miR-147 as highly anti-correlated with an EMT gene expression signature score and postulated to reverse EMT (MET). miR-147 was transfected into colon cancer cells (HCT116, SW480) as well as lung cancer cells (A-549). The cells were assessed for morphological changes, and evaluated for effects on invasion, motility, and the expression of key EMT markers. Resistance to chemotherapy was evaluated by treating cells with gefitinib, an EGFR inhibitor. The downstream genes regulated by miR-147 were assayed using the Affymetrix GeneChip U133 Plus2.0 platform. miR-147 was identified to: 1. cause MET primarily by increasing the expression of CDH1 and decreasing that of ZEB1; 2. inhibit the invasion and motility of cells; 3. cause G1 arrest by up-regulating p27 and down-regulating cyclin D1. miR-147 also dramatically reversed the native drug resistance of the colon cancer cell line HCT116 to gefitinib. miR-147 significantly repressed Akt phosphorylation, and knockdown of Akt with siRNA induced MET. The morphologic effects of miR-147 on cells appear to be attenuated by TGF-B1, promoting a plastic and reversible transition between MET and EMT. miR-147 induced cancer cells to undergo MET and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance. We conclude that miR-147 might have therapeutic potential given its ability to inhibit proliferation, induce MET, as well as reverse drug sensitivity.
    PLoS ONE 01/2014; 9(1):e84597. DOI:10.1371/journal.pone.0084597 · 3.23 Impact Factor
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    ABSTRACT: We present a set of 26 finite quandles that distinguish (up to reversal and mirror image) by number of colorings, all of the 2977 prime oriented knots with up to 12 crossings. We also show that 1058 of these knots can be distinguished from their mirror images by the number of colorings by quandles from a certain set of 23 finite quandles. We study the colorings of these 2977 knots by all of the 431 connected quandles of order at most 35 found by L. Vendramin. Among other things, we collect information about quandles that have the same number of colorings for all of the 2977 knots. For example, we prove that if $Q$ is a simple quandle of prime power order then $Q$ and the dual quandle $Q^*$ of $Q$ have the same number of colorings for all knots and conjecture that this holds for all Alexander quandles $Q$. We study a knot invariant based on a quandle homomorphism $f:Q_1\to Q_0$. We also apply the quandle colorings we have computed to obtain some new results for the bridge index, the Nakanishi index, the tunnel number, and the unknotting number. In an appendix we discuss various properties of the quandles in Vendramin's list. Links to the data computed and various programs in C, GAP and Maple are provided.
    Journal of Knot Theory and Its Ramifications 12/2013; 23(06). DOI:10.1142/S0218216514500357 · 0.41 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):LB-43-LB-43. DOI:10.1158/1538-7445.AM2013-LB-43 · 9.33 Impact Factor
  • Cindy R Timme · Mike Gruidl · Timothy J Yeatman
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    ABSTRACT: The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.
    Apoptosis 07/2013; 18(10). DOI:10.1007/s10495-013-0883-x · 3.69 Impact Factor
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    ABSTRACT: Alpha-fetoprotein (AFP)-secreting hepatocellular carcinomas (HCC) represent a genetically distinct subset of tumors often associated with a worse prognosis. However, the molecular mechanisms that underlie these phenotypic differences remain poorly understood. HCC tumor samples from 27 patients were profiled using the Affymetrix 133 Plus 2.0 GeneChips. GeneGO Metacore software was used to identify altered biologic pathways. Expression validation was confirmed by RT-PCR. Manipulation of miR-675 by overexpression and antagomir-mediated knockdown was carried out with subsequent evaluation of effects on cell behavior by cell cycle, proliferation, invasion, and growth in soft agar assays. We identified a strong relationship between primary tumor H19 gene expression and elevated serum AFP. H19 has recently been identified to encode microRNA-675 (miR-675), and we confirmed the relationship in an independent sample of patients. Pathway analyses of the effect of miR-675 overexpression in hepatoma cells revealed a predominant upregulation of cell adhesion and cell cycle initiation pathways. We have demonstrated that miR-675 mediates increases in proliferation and an accumulation of cells with tetraploid DNA content associated with a repression of Rb. We also demonstrated that overexpression of miR-675 alters cellular morphology, reduces invasive potential, and increases anchorage-independent growth capacity. These findings are consistent with a mesenchymal-to-epithelial transition, associated with a reduction in the expression of the key EMT mediator, Twist1. Expression of the miR-675 in hepatocellular carcinoma links a dramatic upregulation of proliferative and growth capacity with inhibition of motility in HCC cells.
    Annals of Surgical Oncology 07/2013; 20(S3). DOI:10.1245/s10434-013-3106-3 · 3.93 Impact Factor
  • Cancer Research 04/2013; 73(8 Supplement):LB-70-LB-70. DOI:10.1158/1538-7445.AM2013-LB-70 · 9.33 Impact Factor
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    Cancer Research 06/2012; 72(8 Supplement):1156-1156. DOI:10.1158/1538-7445.AM2012-1156 · 9.33 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):435-435. DOI:10.1158/1538-7445.AM2012-435 · 9.33 Impact Factor
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    ABSTRACT: The Notch signalling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN and the downstream target HES1. Thirty-seven patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only six patients had stable disease as their best response. Median PFS was 1.8 months and median overall survival (OS) was 6.0 months. In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.
    European journal of cancer (Oxford, England: 1990) 03/2012; 48(7):997-1003. DOI:10.1016/j.ejca.2012.02.056 · 5.42 Impact Factor
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    ABSTRACT: Altered expression of specific microRNAs (miRNA) is known to occur during colorectal carcinogenesis. However, little is known about the genome-wide alterations in miRNA expression during the neoplastic progression of primary colorectal cancers. Using a miRNA array platform, we evaluated the expression of 668 miRNA in primary colonic adenocarcinomas. Biological functions of selected miRNA were evaluated with in vitro invasion assays. RNA was extracted for miRNA analysis from 65 primary colon cancers. We identified a seven-miRNA expression signature that differentiated stage I and stage IV primary colon cancers. We then demonstrated this signature was able to discriminate between stage II and III primary colon cancers. Six differentially expressed miRNA were downregulated in association with the development of metastases, and all 7 miRNA were complementary strand miRNA. We transfected HCT-116, a highly invasive colon cancer cell line, with corresponding downregulated miRNA and demonstrated that overexpression of three miRNA (miR200c*, miR143*, and miR424*) significantly abrogated invasive potential. We have identified a seven-miRNA signature that is associated with metastatic potential in the primary tumor. Forced overexpression of three downregulated miRNA resulted in attenuation of in vitro invasion, suggesting direct tumor suppressive function and further supporting the biological importance of complementary strand miRNA.
    Journal of Gastrointestinal Surgery 02/2012; 16(5):905-12; discussion 912-3. DOI:10.1007/s11605-011-1815-0 · 2.80 Impact Factor
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    ABSTRACT: In biomedical science, data mining techniques have been applied to extract statistically significant and clinically useful information from a given dataset. Finding biomarker gene sets for diseases can aid in understanding disease diagnosis, prognosis and therapy response. Gene expression microarrays have played an important role in such studies and yet, there have also been criticisms in their analysis. Analysis of these datasets presents the high risk of over-fitting (discovering spurious patterns) because of their feature-rich but case-poor nature. This paper describes a GA-SVM hybrid along with Gaussian noise perturbation (with a manual noise gain) to combat over-fitting; determine the strongest signal in the dataset; and discover stable biomarker sets. A colon cancer gene expression microarray dataset is used to show that the strongest signal in the data (optimal noise gain where a modest number of similar candidates emerge) can be found by a binary search. The diversity of candidates (measured by cluster analysis) is reduced by the noise perturbation, indicating some of the patterns are being eliminated (we hope mostly spurious ones). Initial biological validated has been tested and genes have different levels of significance to the candidates; although the discovered biomarker sets should be studied further to ascertain their biological significance and clinical utility. Furthermore, statistical validity displays that the strongest signal in the data is spurious and the discovered biomarker sets should be rejected.
    Procedia Computer Science 12/2011; 6:153-158. DOI:10.1016/j.procs.2011.08.030

Publication Stats

9k Citations
1,170.43 Total Impact Points


  • 2013–2015
    • Gibbs Cancer Center
      SPA, South Carolina, United States
  • 1970–2014
    • Moffitt Cancer Center
      • • Department of Molecular Oncology
      • • Department of Biostatistics
      Tampa, Florida, United States
  • 1996–2013
    • University of South Florida
      • • Department of Surgery
      • • Department of Pathology and Cell Biology
      • • Morsani College of Medicine
      Tampa, Florida, United States
  • 2011
    • Binghamton University
      • Department of Bioengineering
      Binghamton, NY, United States
  • 2006
    • Tampa General Hospital
      Tampa, Florida, United States
    • The Ohio State University
      Columbus, Ohio, United States
  • 2005
    • George Washington University
      • Department of Biochemistry
      Washington, Washington, D.C., United States
  • 2001
    • Biomedical Research Institute, Rockville
      Роквилл, Maryland, United States
  • 1999
    • St. George's School
      Middletown, Rhode Island, United States
  • 1993–1995
    • University of Texas MD Anderson Cancer Center
      • Department of General Surgery
      Houston, Texas, United States