Publications by authors named "Luis Chiriboga"

97 Publications

Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans.

Commun Biol 2021 Mar 31;4(1):436. Epub 2021 Mar 31.

Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.

Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, through all tissues and organs. Fibrous coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unclear. Here we show evidence for continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized. Both techniques demonstrate interstitial continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.
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http://dx.doi.org/10.1038/s42003-021-01962-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012658PMC
March 2021

Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy.

J Neuropathol Exp Neurol 2021 Jan;80(2):160-168

From the Department of Pathology.

Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.
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http://dx.doi.org/10.1093/jnen/nlaa137DOI Listing
January 2021

Validation of PD-L1 clone 22C3 immunohistochemical stain on two Ventana DISCOVERY autostainer models: detailed protocols, test performance characteristics, and interobserver reliability analyses.

J Histotechnol 2020 12 14;43(4):174-181. Epub 2020 Oct 14.

Department of Pathology, NYU Langone Health , New York, NY, USA.

Immunohistochemical (IHC) stain for PD-L1 as a biomarker for immunotherapy is recommended in non-small cell lung cancer (NSCLC). Under the FDA, the selection of patients for pembrolizumab requires companion diagnostic testing using the Dako Agilent PD-L1 IHC 22C3 pharmDx kit performed on the Dako Autostainer Link 48 platform. However, because it is not widely available, there is need for cross-platform validation. Existing studies provide incomplete protocol detail. In our study, 73 lung tumors were stained using the FDA-approved test ('gold standard'). The same blocks were stained using two different models of the Ventana DISCOVERY platform (ULTRA, n = 73 and XT, n = 70) using different parameters, and interpreted by three pathologists. The ULTRA group met College of American Pathologists (CAP) validation criteria (concordance 91.8%) while the XT group did not (concordance 67.1%). Using tumor proportion score (TPS) ≥1% and TPS ≥50% as cut-offs, the ULTRA protocol had higher sensitivity (97.8% and 91.7%) than XT (73.3% and 60.9%) and similar specificity (ULTRA 88.9% and 100%, XT 88% and 100%). Discordance between ULTRA and XT was 27%, and in all these cases ULTRA was concordant with gold standard. Interobserver reliability was substantial for ULTRA and almost perfect for XT, providing evidence that staining rather than observer variability accounts for XT's inferior performance. Cross-validation of the clinically used 22C3 anti PD-L1 antibody test with substantial interobserver agreement is possible on the commonly used the Ventana DISCOVERY ULTRA automated instrument, while the validation failed on the XT. Cautious attention to detail must be paid when choosing cross-validation parameters.
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http://dx.doi.org/10.1080/01478885.2020.1823105DOI Listing
December 2020

Detection of Cerebrovascular Loss in the Normal Aging C57BL/6 Mouse Brain Using Contrast-Enhanced Magnetic Resonance Angiography.

Front Aging Neurosci 2020 20;12:585218. Epub 2020 Oct 20.

Department of Radiology, Center for Advanced Imaging Innovation and Research (CAI2R), NYU Grossman School of Medicine, New York, NY, United States.

Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents.
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http://dx.doi.org/10.3389/fnagi.2020.585218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606987PMC
October 2020

Keratin 19 and mesenchymal markers for evaluation of epithelial-mesenchymal transition and stem cell niche components in primary biliary cholangitis by sequential elution-stripping multiplex immunohistochemistry.

J Histotechnol 2020 12 1;43(4):163-173. Epub 2020 Oct 1.

Department of Pathology, NYU Langone Health , New York, USA.

Multiplexed immunohistochemical techniques give insight into contextual cellular relationships by offering the ability to collect cell-specific data with spatial information from formalin-fixed, paraffin-embedded tissue sections. We established an automated sequential elution-stripping multiplex immunohistochemical assay to address two controversial scientific questions in the field of hepatopathology: 1) whether epithelial-to-mesenchymal transition or mesenchymal-to-epithelial transition occurs during liver injury and repair of a chronic liver disease and 2) if there is a stromal:epithelial relationship along the canals of Hering that would support the concept of this biliary structure being a stem/progenitor cell niche. Our 4-plex assay includes both epithelial and mesenchymal clinical immunohistochemical markers and was performed on clinical human liver specimens in patients with primary biliary cholangitis. The assay demonstrated that in each specimen, co-expression of epithelial and mesenchymal markers was observed in extraportal cholangiocytes. In regard to possible mesenchymal components in a stem cell niche, 82.3% ± 5.5% of extraportal cholangiocytes were intimately associated with a vimentin-positive cell. Co-expression of epithelial and mesenchymal markers by extraportal cholangiocytes is evidence for epithelial to mesenchymal transition in primary biliary cholangitis. Vimentin-positive stromal cells are frequently juxtaposed to extraportal cholangiocytes, supporting an epithelial:mesenchymal relationship within the hepatobiliary stem cell niche. Our automated sequential elution-stripping multiplex immunohistochemical assay is a cost-effective multiplexing technique that can be readily applied to a small series of clinical pathology samples in order to answer scientific questions involving cell:cell relationships and cellular antibody expression.
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http://dx.doi.org/10.1080/01478885.2020.1807228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704755PMC
December 2020

The diagnostic utility of EZH2 H-score and Ki-67 index in non-invasive breast apocrine lesions.

Pathol Res Pract 2020 Sep 2;216(9):153041. Epub 2020 Jun 2.

Department of Pathology, New York University Langone Health, New York, NY, USA. Electronic address:

In diagnostic breast pathology, there is no reliable applicable immunostain to help discern atypical and in situ apocrine lesions from benign apocrine tissue. At present, the diagnosis of non-invasive apocrine lesions remains challenging with current diagnoses rendered based on discrete morphologic characteristics on conventional hematoxylin and eosin staining. Interobserver variability is significant even among subspecialists partly due to lack of adjuvant diagnostic immunohistochemical stains. Herein, we set to elucidate the potential utility of EZH2 and Ki-67 immunostains as tangible tools in non-invasive apocrine proliferations. A cohort of apocrine breast lesions [Benign apocrine hyperplasia (BAH), n = 10; Atypical apocrine hyperplasia (AAH), n = 16; Apocrine ductal carcinoma in situ (ADCIS), n = 12] were subjected to EZH2 immunostaining and analyzed via H-scoring of nuclear expression. Mean H-scores for EZH2 progressively increased from BAH (23.5), to AAH (47.4) and ADCIS (196.4), and showed a significant difference utilizing the Kruskal-Wallis test (p < 0.0001). Further interrogation of Ki-67 demonstrated incremental expression from BAH to AAH and ADCIS at 1.6 %, 4.7 % and 24.7 %, respectively (p < 0.0001, Kruskal-Wallis test), suggesting an association with increased proliferation. Our results demonstrate that a combination of EZH2 and Ki-67 immunostaining may be employed in differentiating among challenging apocrine breast lesions and suggest a putative diagnostic utility for EZH2 and Ki-67 in non-invasive apocrine breast lesions.
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http://dx.doi.org/10.1016/j.prp.2020.153041DOI Listing
September 2020

Expression profiling of the adhesion G protein-coupled receptor GPR133 (ADGRD1) in glioma subtypes.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa053. Epub 2020 Apr 28.

Departments of Neurosurgery, New York, New York, USA.

Background: Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown.

Methods: We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas.

Results: We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors.

Conclusion: The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.
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http://dx.doi.org/10.1093/noajnl/vdaa053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262742PMC
April 2020

Experimental Variables that Affect Human Hepatocyte AAV Transduction in Liver Chimeric Mice.

Mol Ther Methods Clin Dev 2020 Sep 2;18:189-198. Epub 2020 Jun 2.

Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.

Adeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene expression in such models remain poorly defined. Here, we aimed to test whether three experimental conditions influence AAV transgene expression in immunodeficient, fumaryl-acetoactetate-hydrolase-deficient () chimeric mice repopulated with primary human hepatocytes. We examined the effects of the murine liver injury cycle, human donor variability, and vector doses on hepatocyte transduction with various AAV serotypes expressing a green fluorescent protein (GFP). We determined that the timing of AAV vector challenge in the liver injury cycle resulted in up to 7-fold differences in the percentage of GFP expressing human hepatocytes. The GFP+ hepatocyte frequency varied 7-fold between human donors without, however, changing the relative transduction efficiency between serotypes for an individual donor. There was also a clear relationship between AAV vector doses and human hepatocyte transduction and transgene expression. We conclude that several experimental variables substantially affect human hepatocyte transduction in the chimera model, attention to which may improve reproducibility between findings from different laboratories.
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http://dx.doi.org/10.1016/j.omtm.2020.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326722PMC
September 2020

Expansion, in vivo-ex vivo cycling, and genetic manipulation of primary human hepatocytes.

Proc Natl Acad Sci U S A 2020 01 8;117(3):1678-1688. Epub 2020 Jan 8.

Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065;

Primary human hepatocytes (PHHs) are an essential tool for modeling drug metabolism and liver disease. However, variable plating efficiencies, short lifespan in culture, and resistance to genetic manipulation have limited their use. Here, we show that the pyrrolizidine alkaloid retrorsine improves PHH repopulation of chimeric mice on average 10-fold and rescues the ability of even poorly plateable donor hepatocytes to provide cells for subsequent ex vivo cultures. These mouse-passaged (mp) PHH cultures overcome the marked donor-to-donor variability of cryopreserved PHH and remain functional for months as demonstrated by metabolic assays and infection with hepatitis B virus and mpPHH can be efficiently genetically modified in culture, mobilized, and then recultured as spheroids or retransplanted to create highly humanized mice that carry a genetically altered hepatocyte graft. Together, these advances provide flexible tools for the study of human liver disease and evaluation of hepatocyte-targeted gene therapy approaches.
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http://dx.doi.org/10.1073/pnas.1919035117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983380PMC
January 2020

Test your knowledge.

J Histotechnol 2019 12;42(4):246-247

NYU Langone Health Center, Center for Biospecimen Research and Development, New York, NY, USA.

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http://dx.doi.org/10.1080/01478885.2019.1660109DOI Listing
December 2019

The changing landscape of scientific publishing.

Authors:
Luis Chiriboga

J Histotechnol 2019 09;42(3):95-97

Department of Pathology, NYU School of Medicine , New York , NY , USA.

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http://dx.doi.org/10.1080/01478885.2019.1636554DOI Listing
September 2019

Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod.

Sci Rep 2019 06 12;9(1):8572. Epub 2019 Jun 12.

Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York, USA.

Imiquimod is a topical toll-like-receptor-7 agonist currently used for treating basal cell carcinoma. Recently, imiquimod has demonstrated tumor regression in melanoma and breast cancer skin metastases. However, the molecular perturbations induced by imiquimod in breast cancer metastases have not been previously characterized. Here, we describe transcriptomic profiles associated with responsiveness to imiquimod in breast cancer skin metastases. Baseline and post-treatment tumor samples from patients treated with imiquimod in a clinical trial were profiled using Nanostring technology. Through an integrative analytic pipeline, we showed that tumors from patients who achieved a durable clinical response displayed a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, characterized by the coordinated upregulation of Th-1 chemokines, migration of Th-1 and cytotoxic T cells into the tumor, and activation of immune-effector functions, ultimately mediating tumor destruction. In conclusion, we have shown that topical imiquimod can induce a robust immune response in breast cancer metastases, and this response is more likely to occur in tumors with a pre-activated microenvironment. In this setting, imiquimod could be utilized in combination with other targeted immunotherapies to increase therapeutic efficacy.
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http://dx.doi.org/10.1038/s41598-019-42784-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561945PMC
June 2019

Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids.

Cell 2018 11;175(6):1591-1606.e19

Oncode Institute, Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands; University Medical Center Utrecht, Cancer Genomics Netherlands, 3584CX Utrecht, the Netherlands; The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address:

The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The "oval cell" response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes.
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http://dx.doi.org/10.1016/j.cell.2018.11.013DOI Listing
November 2018

Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma.

Clin Cancer Res 2019 02 5;25(4):1261-1271. Epub 2018 Nov 5.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York.

Purpose: Isocitrate dehydrogenase ()-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90% -mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in -mutant glioma.

Experimental Design: We evaluated expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous -mutant glioma tumorspheres was determined by cell viability assay.

Results: Compared to wild-type glioblastoma, -mutant gliomas have significantly higher RNA ( < 1 × 10) and protein by IHC ( = 0.0014 and < 4.3 × 10 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in -mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived -mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.

Conclusions: DLL3 is selectively and homogeneously expressed in -mutant gliomas and can be targeted with Rova-T in patient-derived -mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365589PMC
February 2019

Durable response to anti-PD-1 immunotherapy in epithelioid angiomyolipoma: a report on the successful treatment of a rare malignancy.

J Immunother Cancer 2018 10 1;6(1):97. Epub 2018 Oct 1.

Department of Medicine, NYU Langone Health, New York, NY, USA.

Background: Malignant angiomyolipoma is an uncommon tumor of the class of perivasciular epithelioid cell neoplasms (PEComas). These tumors are characteristically driven by deleterious mutations in the tumor suppressors TSC1 and TSC2, whose gene products typically act to inhibit mTOR. There are several cases of malignant angiomyolipoma which exhibit transient responses to mTOR inhibitors, forming the basis of current practice guidelines in malignant PEComa. However the tumors ultimately acquire resistance, and there is no well-established second-line option. Despite the increasing prevalence of immunotherapy across a wide range of solid tumors, little is known about the immune infiltrate and PD-L1 expression of angiomyolipoma. Furthermore, there is no reported case on the treatment of malignant angiomyolipoma with an immune checkpoint inhibitor.

Case Presentation: A 38 year-old man presented with gross hematuria and was diagnosed with renal epithelioid angiomyolipoma. Despite surgical resection, the tumor recurred and metastasized. Targeted genomic sequencing revealed a deleterious mutation in TSC2, and the patient was treated with the mTOR inihbitor everolimus. The patient went on to have a partial response but ultimately progressed. He was then treated with the anti-PD-1 immune checkpoint inhibitor nivolumab, and achieved a durable near-complete response which is ongoing after two years of treatment. Immunohistochemical staining of tumor tissue revealed strong PD-L1 expression and a brisk T-cell infiltrate.

Conclusions: We report on the first durable systemic treatment of malignant epithelioid angiomyolipoima with the use of PD-1 antibody nivolumab. Given the absence of prospective clinical trials in this exceedingly rare disease, particularly in the second-line setting, immune checkpoint inhibitors like nivolumab should be considered.
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http://dx.doi.org/10.1186/s40425-018-0415-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167873PMC
October 2018

Chibby is a weak regulator of β-catenin activity in gastric epithelium.

J Cell Physiol 2019 02 31;234(2):1871-1879. Epub 2018 Jul 31.

Department of Medical Laboratory Sciences, Hunter College, School of Arts and Sciences, New York.

The canonical Wnt-β-catenin pathway is important in normal development. Mutations in β-catenin or proteins involved with regulating its phosphorylation or localization result in its nuclear accumulation where it activates its target genes and stimulates cell proliferation. This pathway is dysregulated in many different types of cancer, including gastric cancer (GC). Chibby (Cby) is a 14-kDa protein that inhibits β-catenin localization to the nucleus and represses β-catenin-induced transcriptional activity. In the current study, we examined the expression and function of Cby in normal and cancerous human gastric tissue. Reverse-transcription polymerase chain reaction and immunohistochemistry revealed that Cby is expressed in human stomach and localized to glandular elements. Immunohistochemical staining intensity of Cby was decreased in GC tissue when compared with normal gastric epithelium. In AGS cells, a human gastric carcinoma cell line, Cby expression was low. Stable AGS cell transfectants overexpressing Cby were prepared. Cby overexpression did not affect proliferation rates or β-catenin levels. However, confocal microscopy and subcellular fractionation studies revealed that Cby overexpression resulted in a small decrease in nuclear β-catenin. Moreover, Cby overexpression caused a molecular weight shift in nuclear β-catenin and resulted in decreased β-catenin signaling in AGS cells as measured by the TopFlash assay. However, Cby overexpression did not affect c-Myc protein levels. To conclude, Cby expression was decreased in GC samples and Cby expression altered β-catenin localization in cultured GC cells. However, Cby did not affect cell proliferation rates or β-catenin-induced protein expression. Cby may be involved in the early events in the pathogenesis of GC.
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http://dx.doi.org/10.1002/jcp.27062DOI Listing
February 2019

Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma.

Nat Commun 2018 07 20;9(1):2868. Epub 2018 Jul 20.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
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http://dx.doi.org/10.1038/s41467-018-05029-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054684PMC
July 2018

Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.

Sci Transl Med 2018 06;10(447)

Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA.

Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics.
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http://dx.doi.org/10.1126/scitranslmed.aap9328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337727PMC
June 2018

Targeting Poxvirus Decapping Enzymes and mRNA Decay to Generate an Effective Oncolytic Virus.

Mol Ther Oncolytics 2018 Mar 31;8:71-81. Epub 2018 Jan 31.

Department of Microbiology, NYU School of Medicine, New York, NY, USA.

Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy.
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http://dx.doi.org/10.1016/j.omto.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991893PMC
March 2018

Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas.

Am J Surg Pathol 2018 08;42(8):989-1000

Memorial Sloan Kettering Cancer Center.

The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus-associated (HPVA) and non-human papilloma virus-associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus-associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.
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http://dx.doi.org/10.1097/PAS.0000000000001090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041133PMC
August 2018

Membrane attack complex (mac) deposition in lupus nephritis is associated with hypertension and poor clinical response to treatment.

Semin Arthritis Rheum 2018 10 6;48(2):256-262. Epub 2018 Jan 6.

Medicine, Division of Rheumatology, NYU Langone Health, 301 East 17th St, Suite 1410, New York, NY 10003.

Objective: To study membrane attack complex in lupus nephritis as a potential biomarker for disease intensity and prognostic indicator for response to treatment.

Methods: Immunohistochemistry was performed using unconjugated, murine anti-human complement C9 on kidney biopsies from 30 SLE patients who fulfilled 4 ACR or SLICC criteria. Clinical parameters were assessed at time of biopsy, 6 and 12 months.

Results: 30 renal biopsies were obtained from patients with Class II (2), III (5), IV (8), V (5), III+V (8) and IV+V (2). 13/30 (43.3%) biopsies stained positive for glomerular C9. Patients with positive C9 had significantly higher blood pressure, trend towards lower C3, and male gender. There was no significant difference for ISN/RPN class, activity or chronicity indices between C9 positive and negative groups. 5/11 (45.5%) patients positive for C9 did not respond to therapy at 6 months compared with 2/15 (13.3%) patients negative for C9. C9 positive patients were more likely to be a non-responder at 6 months (OR = 5.4, 95% CI: 0.8, 36.4) compared to C9 negative patients. After adjusting for systolic blood pressure, compliance to treatment and proteinuria in a multivariate logistic model, C9 positive patients remained more likely to be non-responders (OR = 4.6, 95% CI: 0.3, 70.9).

Conclusion: This study suggests that MAC deposition measured as C9 staining may be a biomarker for more intense disease and poor response to treatment in lupus nephritis. MAC staining may be useful in routine studies of lupus biopsies and identify patients at risk for aggressive disease who may be candidates for novel therapies targeting terminal complement pathway.
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http://dx.doi.org/10.1016/j.semarthrit.2018.01.004DOI Listing
October 2018

Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2.

Cell Rep 2017 Oct;21(5):1267-1280

Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Department of Neurology, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA.

Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.
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http://dx.doi.org/10.1016/j.celrep.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687844PMC
October 2017

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Oncotarget 2017 Sep 23;8(39):64932-64953. Epub 2017 May 23.

Department of Neurosurgery, NYU School of Medicine, New York, NY, USA.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.
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http://dx.doi.org/10.18632/oncotarget.18117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630302PMC
September 2017

Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti-Vascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination.

Am J Pathol 2017 Sep 20;187(9):2080-2094. Epub 2017 Jul 20.

Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York; Division of Neuropathology, New York University Langone Medical Center, New York, New York; Department of Neurosurgery, New York University Langone Medical Center, New York, New York; New York University Langone Laura and Isaac Perlmutter Cancer Center, New York, New York. Electronic address:

Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti-vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1α, and reduced hypoxia- and stromal cell-derived factor-1α-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients.
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http://dx.doi.org/10.1016/j.ajpath.2017.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809520PMC
September 2017

Mouse models of acute and chronic hepacivirus infection.

Science 2017 07;357(6347):204-208

Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.

An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections in laboratory mice with immunological features resembling those seen in human viral hepatitis. Whereas immune-compromised mice developed persistent infection, immune-competent mice cleared the virus within 3 to 5 weeks. Acute clearance was T cell dependent and associated with liver injury. Transient depletion of CD4 T cells before infection resulted in chronic infection, characterized by high levels of intrahepatic regulatory T cells and expression of inhibitory molecules on intrahepatic CD8 T cells. Natural killer cells controlled early infection but were not essential for viral clearance. This model may provide mechanistic insights into hepatic antiviral immunity, a prerequisite for the development of HCV vaccines.
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http://dx.doi.org/10.1126/science.aal1962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654634PMC
July 2017

Arrested Development: Infantile Hemangioma and the Stem Cell Teratogenic Hypothesis.

Lymphat Res Biol 2017 06 18;15(2):153-165. Epub 2017 May 18.

4 Department of Medicine, New York University School of Medicine , New York, New York.

Background: Early-life programming is defined by the adaptive changes made by the fetus in response to an adverse in utero environment. Infantile hemangioma (IH), a vascular anomaly, is the most common tumor of infancy. Here we take IH as the tumor model to propose the stem cell teratogenic hypothesis of tumorigenesis and the potential involvement of the immune system.

Objectives: Teratogenic agents include chemicals, heavy metals, pathogens, and ionizing radiation. To investigate the etiology and pathogenesis of IH, we hypothesized that they result from a teratogenic mechanism. Immature, incompletely differentiated, dysregulated progenitor cells (multipotential stem cells) are arrested in development with vasculogenic, angiogenic, and tumorigenic potential due to exposure to teratogenic agents such as extrinsic factors that disrupt intrinsic factors via molecular mimicry. During the critical period of immunological tolerance, environmental exposure to immunotoxic agents may harness the teratogenic potential in the developing embryo or fetus and modify the early-life programming algorithm by altering normal fetal development, causing malformations, and inducing tumorigenesis. Specifically, exposure to environmental agents may interfere with physiological signaling pathways and contribute to the generation of IH, by several mechanisms.

Discussion: An adverse in utero environment no longer serves as a sustainable environment for proper embryogenesis and normal development. Targeted disruption of stem cells by extrinsic factors can alter the genetic program.

Conclusions: This article offers new perspectives to stimulate discussion, explore novel experimental approaches (such as immunotoxicity/vasculotoxicity assays and novel isogenic models), and to address the questions raised to convert the hypotheses into nontoxic, noninvasive treatments.
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http://dx.doi.org/10.1089/lrb.2016.0030DOI Listing
June 2017

Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase.

Mol Cancer Res 2017 09 16;15(9):1138-1152. Epub 2017 May 16.

Department of Medicine, Division of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, New York.

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific -null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33 MDSCs. This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581693PMC
September 2017

Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection.

Virology 2017 02 19;502:63-72. Epub 2016 Dec 19.

Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey, NJ 08544, USA. Electronic address:

There are ~350 million chronic carriers of hepatitis B (HBV). While a prophylactic vaccine and drug regimens to suppress viremia are available, chronic HBV infection is rarely cured. HBV's limited host tropism leads to a scarcity of susceptible small animal models and is a hurdle to developing curative therapies. Mice that support engraftment with human hepatoctyes have traditionally been generated through crosses of murine liver injury models to immunodeficient backgrounds. Here, we describe the disruption of fumarylacetoacetate hydrolase directly in the NOD Rag1 IL2RγNULL (NRG) background using zinc finger nucleases. The resultant human liver chimeric mice sustain persistent HBV viremia for >90 days. When treated with standard of care therapy, HBV DNA levels decrease below detection but rebound when drug suppression is released, mimicking treatment response observed in patients. Our study highlights the utility of directed gene targeting approaches in zygotes to create new humanized mouse models for human diseases.
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http://dx.doi.org/10.1016/j.virol.2016.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414730PMC
February 2017

Nuclear TBLR1 as an ER corepressor promotes cell proliferation, migration and invasion in breast and ovarian cancer.

Am J Cancer Res 2016 1;6(10):2351-2360. Epub 2016 Oct 1.

Department of Pathology, New York University School of MedicineNew York, NY; Department of Urology, New York University School of MedicineNew York, NY; Department of NYU Cancer Institute, New York University School of MedicineNew York, NY; Department of New York Harbor Healthcare System, New York University School of MedicineNew York, NY.

Estrogen receptors (ER) play important roles in the development and progression of breast and ovarian cancers. ERs mediate transcriptional regulation through interaction with cofactors and binding to response elements within the regulatory elements of target genes. Here, we examined the expression and function of TBLR1/TBL1XR1, a core component of NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid receptor) corepressor complexes, in breast and ovarian cancers. We found that although TBLR1 is present in both the nucleus and cytoplasm of normal and neoplastic breast and ovarian cells, it is expressed at significantly higher levels in the nucleus of malignant breast and ovarian cells compared to benign cells. TBLR1 functions as an ER corepressor to inhibit ER-mediated transcriptional activation in both breast and ovarian cell lines, but it has no effect on androgen receptor (AR) mediated transcriptional activation in these cells. Furthermore, ectopic expression of nuclear TBLR1 in breast and ovarian cancer cells stimulates cell proliferation. The increased cell proliferation by nuclear TBLR1 is through both ER-independent and ER-dependent mechanisms as evidenced by increased growth in hormone-free medium and estrogen medium, as well as reduced growth with ER knockdown by siRNA. Nuclear TBLR1 overexpression also increased migration and invasion in both breast and ovarian cancer cells. Determining the functional relationship between TBLR1 and ER may provide insights to develop novel treatment strategies and improve response to hormonal therapy in breast and ovarian cancers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088298PMC
October 2016

Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell.

Sci Rep 2016 10 27;6:35811. Epub 2016 Oct 27.

Department of Medicine, New York University School of Medicine, 550 First Avenue New York, NY 10016, USA.

Infantile hemangioma (IH) is the most common tumor of infancy. Its cellular origin and biological signals for uncontrolled growth are poorly understood, and specific pharmacological treatment is unavailable. To understand the process of hemangioma-genesis we characterized the progenitor hemangioma-derived stem cell (HemSC) and its lineage and non-lineage derivatives. For this purpose we performed a high-throughput (HT) phenotypic and gene expression analysis of HemSCs, and analyzed HemSC-derived tumorspheres. We found that IH is characterized by high expression of genes involved in vasculogenesis, angiogenesis, tumorigenesis and associated signaling pathways. These results show that IH derives from a dysregulated stem cell that remains in an immature, arrested stage of development. The potential biomarkers we identified can afford the development of diagnostic tools and precision-medicine therapies to "rewire" or redirect cellular transitions at an early stage, such as signaling pathways or immune response modifiers.
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http://dx.doi.org/10.1038/srep35811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081534PMC
October 2016