Heidi L Weiss

University of Kentucky, Lexington, Kentucky, United States

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Publications (163)1021.86 Total impact

  • PLoS ONE 04/2015; 10(4):e0124988. DOI:10.1371/journal.pone.0124988 · 3.53 Impact Factor
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    ABSTRACT: Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells and orthotopic CRCs. Immunohistochemical evaluation demonstrated increased expression of FASN and p62, a marker of autophagy inhibition, in primary CRCs and liver metastases compared to matched normal colonic mucosa. Our findings indicate that overexpression of FASN plays a crucial role in maintaining energy homeostasis in CRC via increased oxidation of endogenously synthesized lipids. Importantly, activation of fatty acid oxidation and consequent downregulation of stress-response signaling pathways may be key adaptation mechanisms that mediate the effects of FASN on cancer cell survival and metastasis, providing a strong rationale for targeting this pathway in advanced CRC.
    Oncotarget 04/2015; · 6.63 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-933. DOI:10.1016/S0016-5085(15)33178-4 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-342-S-343. DOI:10.1016/S0016-5085(15)31143-4 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-41. DOI:10.1016/S0016-5085(15)30142-6 · 13.93 Impact Factor
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    ABSTRACT: The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of intestinal epithelium homeostasis by regulating Notch activity.
    Cell Death & Disease 02/2015; 6(2):e1631. DOI:10.1038/cddis.2014.588 · 5.18 Impact Factor
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    ABSTRACT: The majority of deaths from all cancers, including colorectal cancer (CRC), is a result of tumor metastasis to distant organs. To date, an effective and safe system capable of exclusively targeting metastatic cancers that have spread to distant organs or lymph nodes does not exist. Here, we constructed multifunctional RNA nanoparticles, derived from the three-way junction (3WJ) of bacteriophage phi29 motor pRNA, to target metastatic cancer cells in a clinically relevant mouse model of CRC metastasis. The RNA nanoparticles demonstrated metastatic tumor homing without accumulation in normal organ tissues surrounding metastatic tumors. The RNA nanoparticles simultaneously targeted CRC cancer cells in major sites of metastasis, such as liver, lymph nodes and lung. Our results demonstrate the therapeutic potential of these RNA nanoparticles as a delivery system for the treatment of CRC metastasis.
    ACS Nano 02/2015; 9(2). DOI:10.1021/acsnano.5b00067 · 12.03 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):1009-1009. DOI:10.1158/1538-7445.AM2014-1009 · 9.28 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located approximately 900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2014; 136(6). DOI:10.1002/ijc.29123 · 5.01 Impact Factor
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    ABSTRACT: Autophagy is a tightly regulated lysosomal degradation pathway for maintaining cellular homeostasis and responding to stresses. Beclin 1 and its interacting proteins, including the class III phosphatidylinositol-3 kinase Vps34, play crucial roles in autophagy regulation in mammals. We identified nuclear receptor binding factor 2 (Nrbf2) as a Beclin 1-interacting protein from Becn1-/-;Becn1-EGFP/+ mouse liver and brain. We also found that Nrbf2-Beclin 1 interaction required the N-terminus of Nrbf2. We next used human retinal pigment epithelial cell line RPE-1 as a model system and showed that transiently knocking down Nrbf2 by siRNA increased autophagic flux under both nutrient-rich and starvation conditions. To investigate the mechanism by which Nrbf2 regulates autophagy, we demonstrated that Nrbf2 interacted and colocalized with Atg14L, suggesting that Nrbf2 is a component of the Atg14L-containing Beclin 1-Vps34 complex. Moreover, ectopically expressed Nrbf2 formed cytosolic puncta that were positive for isolation membrane markers. These results suggest that Nrbf2 is involved in autophagosome biogenesis. Furthermore, we showed that Nrbf2 deficiency led to increased intracellular phosphatidylinositol-3 phosphate levels as well as diminished Atg14L-Vps34/Vps15 interactions, suggesting that Nrbf2-mediated Atg14L-Vps34/Vps15 interactions likely inhibit Vps34 activity. Therefore, we propose that Nrbf2 may interact with the Atg14L-containing Beclin 1-Vps34 protein complex to modulate protein-protein interactions within the network, leading to suppression of Vps34 activity, autophagosome biogenesis and autophagic flux. This work reveals a novel aspect of the intricate mechanism for the Beclin 1-Vps34 protein-protein interaction network to achieve precise control of autophagy.
    Journal of Biological Chemistry 08/2014; 289(38). DOI:10.1074/jbc.M114.561134 · 4.60 Impact Factor
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    ABSTRACT: The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here, we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor REDD1 protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mTOR signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway.
    Molecular Biology of the Cell 07/2014; 25(18). DOI:10.1091/mbc.E14-05-0998 · 4.55 Impact Factor
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    ABSTRACT: Background: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. Materials & methods: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. Results: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. Conclusion: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.
    Future Oncology 05/2014; 10(15):1-14. DOI:10.2217/fon.14.99 · 2.61 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-299. DOI:10.1016/S0016-5085(14)61074-X · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-87. DOI:10.1016/S0016-5085(14)60312-7 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-659. DOI:10.1016/S0016-5085(14)62399-4 · 13.93 Impact Factor
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    ABSTRACT: Up-regulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the Chick Embryo Chorioallantoic Membrane (CAM), and Matrigel plug models using immunohistochemistry, immunofluorescent staining, and confocal microscopy. Cell secretion was evaluated by ELISA and Antibody Arrays. Proliferation, migration, and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC co-culture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in (")normalization(") of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and anti-angiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the anti-angiogenic activity noted with knockdown of FASN included: down-regulation of VEGF(189), up-regulation of anti-angiogenic isoform VEGF(165b), and a decrease in expression and activity of MMP-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of VEGFR-2 and its downstream signaling and decreased proliferation, migration, and tubulogenesis of ECs as compared to control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC.
    Carcinogenesis 02/2014; 35(6). DOI:10.1093/carcin/bgu042 · 5.27 Impact Factor
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    ABSTRACT: The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. The purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.
    Clinical Cancer Research 01/2014; 20(5). DOI:10.1158/1078-0432.CCR-13-1897 · 8.19 Impact Factor
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    ABSTRACT: We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2mg/m(2) with once weekly idarubicin 10mg/m(2) for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8mg/m(2) and idarubicin 10mg/m(2)); idarubicin was reduced to 8mg/m(2) without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2mg/m(2) and idarubicin 8mg/m(2). Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.
    Leukemia research 09/2013; 37(11). DOI:10.1016/j.leukres.2013.09.003 · 2.69 Impact Factor
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    ABSTRACT: Commercialization within the academic setting is associated with many challenges and barriers. Previous studies investigating these challenges/barriers have, in general, broadly focused on multiple disciplines and, oftentimes, several institutions simultaneously. The goal of the study presented here was to analyze a range of barriers that may be broadly associated with commercializing academic-based cancer research. This goal was addressed via a study of the barriers associated with cancer research commercialization at the University of Kentucky (UK). To this end, a research instrument in the form of an electronic survey was developed. General demographic information was collected on study participants and two research questions were addressed: 1) What are the general barriers inhibiting cancer research commercialization at UK? and 2) Would mitigation of the barriers potentially enhance faculty engagement in commercialization activities? Descriptive and statistical analysis of the data reveal that multiple barriers likely inhibit cancer research commercialization at UK with expense, time, infrastructure, and lack of industry partnerships being among the most commonly cited factors. The potential alleviation of these factors in addition to revised University policies/procedures, risk mitigation, more emphasis on commercialization by academia research field, and increased information on how to commercialize significantly correlated with the potential for increased commercialization activity. Furthermore, multivariate logistic regression modeling demonstrated that research commercialization would incrementally increase as barriers to the process are removed and that PhD-holding respondents and respondents in commercialization-supportive research fields would be more likely to commercialize their research upon barrier removal. Overall, as with other disciplines, these data suggest that for innovations derived from academic cancer-research to move more effectively and efficiently into the marketplace, university administrators and external agents, such as policymakers, need to address what are well-documented and defined issues.
    PLoS ONE 08/2013; 8(8):e72268. DOI:10.1371/journal.pone.0072268 · 3.53 Impact Factor
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    ABSTRACT: Paclitaxel (PTX) nanocrystals (200nm) were produced by crystallization from solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48hours by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for hybrid nanocrystals, in tracking drug distribution and pharmacokinetics.
    Journal of Controlled Release 08/2013; 172(1). DOI:10.1016/j.jconrel.2013.06.039 · 7.26 Impact Factor

Publication Stats

6k Citations
1,021.86 Total Impact Points


  • 2009–2015
    • University of Kentucky
      • • Markey Cancer Center
      • • Department of Surgery
      • • Lucille Parker Markey Cancer Center
      • • Department of Biostatistics
      Lexington, Kentucky, United States
  • 2009–2011
    • University of Texas Medical Branch at Galveston
      • • Department of Otolaryngology
      • • Department of Surgery
      • • Department of Preventive Medicine & Community Health
      Galveston, Texas, United States
  • 2004–2010
    • Baylor College of Medicine
      • • Dan L. Duncan Cancer Center
      • • Center for Cell and Gene Therapy
      • • Department of Molecular & Cellular Biology
      Houston, Texas, United States
    • Baylor University
      Waco, Texas, United States
  • 2008
    • Texas Children's Hospital
      Houston, Texas, United States
  • 2005–2007
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 1996–2004
    • University of Alabama at Birmingham
      • • Comprehensive Cancer Center
      • • Department of Medicine
      Birmingham, Alabama, United States