40 results on '"Jackson HW"'
Search Results
2. Structural and Optical Properties of ZnO and MgZnO Semiconductor Materials at Different Annealing Temperature
- Author
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Jackson HW Chang
- Subjects
Multidisciplinary - Published
- 2020
3. Abstract P3-07-11: Withdrawn
- Author
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Jackson, HW, primary, Fischer, JR, additional, Zanotelli, VR, additional, Soysal, SD, additional, Simone, M, additional, Weber, WP, additional, and Bodenmiller, B, additional
- Published
- 2019
- Full Text
- View/download PDF
4. Allyl Chloride (3-Chloro-1-propene) CH2=CHCH2CI
- Author
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Jackson Hw, Husted Fb, and Larocque Wr
- Subjects
3-chloro-1-propene ,Allyl chloride ,chemistry.chemical_compound ,Chemistry ,Public Health, Environmental and Occupational Health ,Organic chemistry - Published
- 1963
5. Allyl Alcohol (2-Propen-1-ol) CH2=CHCH2OH
- Author
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Husted Fb, Jackson Hw, and Larocque Wr
- Subjects
chemistry.chemical_compound ,chemistry ,Public Health, Environmental and Occupational Health ,Organic chemistry ,Allyl alcohol - Published
- 1963
6. Saturation and parabolic effects of langley calibration at different altitude levels
- Author
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Jackson HW Chang, Maizan, N. H. N., Chee, F. P., Sentian, J., Kong, S. S. K., and Dayou, J.
7. Upwelling event characteristics of chlorophyll-a concentration in the surface layer of Sabah waters
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Jackson HW Chang, Francis, A. S., Dayou, J., Sentian, J., and Chee, F. P.
8. Testing a Nanoparticle Reagent for Imaging Mass Cytometry.
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Abtahi M, Gheiratmand L, Dinesh A, Liu Y, Wong ECN, Cho H, Majonis D, Jackson HW, Mrkonjic M, and Winnik MA
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- Humans, Breast Neoplasms pathology, Image Cytometry methods, Female, Polyethylene Glycols chemistry, Fluorides chemistry, Yttrium chemistry, Nanoparticles chemistry
- Abstract
Mass cytometry (MC), a powerful single-cell analysis technique, has limitations in detecting low-abundance biomarkers. Nanoparticle (NP) reagents offer the potential for enhancing sensitivity by carrying large numbers of heavy metal isotopes. Here, we report NP reporters for imaging mass cytometry (IMC) based on NaYF
4 :Yb3+ /Er3+ NPs. A two-step ligand exchange was used to coat NP surfaces with either methoxy-PEG2K -neridronate (PEG-Ner) and/or poly(sulfobetaine methacrylate)-neridronate (PSBMA-Ner). Both modifications provided long-term colloidal stability in PBS buffer. IMC measurements on tonsil tissue showed that PSBMA-Ner or a 1:1 mixture of PSBMA-Ner + PEG-Ner effectively suppressed nonspecific binding (NSB) at 2 × 1010 NPs/mL, unlike PEG-Ner alone. However, breast cancer tissue samples showed increased NSB at titers above 2 × 1010 NPs/mL. Reduced NSB with mixed PEG-Ner and PSBMA-Ner coatings opens the door for using heterobifunctional PEGs for the development of NP conjugates with bioaffinity agents, enabling more sensitive and specific MC analyses.- Published
- 2024
- Full Text
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9. Single-cell atlas of the human brain vasculature across development, adulthood and disease.
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Wälchli T, Ghobrial M, Schwab M, Takada S, Zhong H, Suntharalingham S, Vetiska S, Gonzalez DR, Wu R, Rehrauer H, Dinesh A, Yu K, Chen ELY, Bisschop J, Farnhammer F, Mansur A, Kalucka J, Tirosh I, Regli L, Schaller K, Frei K, Ketela T, Bernstein M, Kongkham P, Carmeliet P, Valiante T, Dirks PB, Suva ML, Zadeh G, Tabar V, Schlapbach R, Jackson HW, De Bock K, Fish JE, Monnier PP, Bader GD, and Radovanovic I
- Subjects
- Female, Humans, Male, Cell Communication, HLA-D Antigens metabolism, Adult, Health, Brain blood supply, Brain pathology, Brain embryology, Brain metabolism, Brain Neoplasms blood supply, Brain Neoplasms pathology, Endothelial Cells metabolism, Endothelial Cells pathology, Endothelial Cells cytology, Fetus blood supply, Fetus cytology, Fetus embryology, RNA-Seq, Single-Cell Gene Expression Analysis, Central Nervous System Vascular Malformations pathology
- Abstract
A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood
1 . Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies., (© 2024. Crown.)- Published
- 2024
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10. Signal amplification by cyclic extension enables high-sensitivity single-cell mass cytometry.
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Lun XK, Sheng K, Yu X, Lam CY, Gowri G, Serrata M, Zhai Y, Su H, Luan J, Kim Y, Ingber DE, Jackson HW, Yaffe MB, and Yin P
- Abstract
Mass cytometry uses metal-isotope-tagged antibodies to label targets of interest, which enables simultaneous measurements of ~50 proteins or protein modifications in millions of single cells, but its sensitivity is limited. Here, we present a signal amplification technology, termed Amplification by Cyclic Extension (ACE), implementing thermal-cycling-based DNA in situ concatenation in combination with 3-cyanovinylcarbazole phosphoramidite-based DNA crosslinking to enable signal amplification simultaneously on >30 protein epitopes. We demonstrate the utility of ACE in low-abundance protein quantification with suspension mass cytometry to characterize molecular reprogramming during the epithelial-to-mesenchymal transition as well as the mesenchymal-to-epithelial transition. We show the capability of ACE to quantify the dynamics of signaling network responses in human T lymphocytes. We further present the application of ACE in imaging mass cytometry-based multiparametric tissue imaging to identify tissue compartments and profile spatial aspects related to pathological states in polycystic kidney tissues., (© 2024. The Author(s).)
- Published
- 2024
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11. Design Parameters for a Mass Cytometry Detectable HaloTag Ligand.
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Potter N, Latour S, Wong ECN, Winnik MA, Jackson HW, McGuigan AP, and Nitz M
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- Humans, Ligands, Kinetics, HEK293 Cells, Proteins, Polymers, Hydrolases
- Abstract
Mass cytometry permits the high dimensional analysis of complex biological samples; however, some techniques are not yet integrated into the mass cytometry workflow due to reagent availability. The use of self-labeling protein systems, such as HaloTag, are one such application. Here, we describe the design and implementation of the first mass cytometry ligands for use with HaloTag. "Click"-amenable HaloTag warheads were first conjugated onto poly(l-lysine) or poly(acrylic acid) polymers that were then functionalized with diethylenetriaminepentaacetic acid (DTPA) lutetium metal chelates. Kinetic analysis of the HaloTag labeling rates demonstrated that the structure appended to the 1-chlorohexyl warhead was key to success. A construct with a diethylene glycol spacer appended to a benzamide gave similar rates ( k
obs ∼ 102 M-1 s-1 ), regardless of the nature of the polymer. Comparison of the polymer with a small molecule chelate having rapid HaloTag labeling kinetics ( kobs ∼ 104 M-1 s-1 ) suggests the polymers significantly reduced the HaloTag labeling rate. HEK293T cells expressing surface-exposed GFP-HaloTag fusions were labeled with the polymeric constructs and175 Lu content measured by cytometry by time-of-flight (CyTOF). Robust labeling was observed; however, significant nonspecific binding of the constructs to cells was also present. Heavily pegylated polymers demonstrated that nonspecific binding could be reduced to allow cells bearing the HaloTag protein to be distinguished from nonexpressing cells.- Published
- 2024
- Full Text
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12. Author Correction: In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.
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Dervovic D, Malik AA, Chen ELY, Narimatsu M, Adler N, Afiuni-Zadeh S, Krenbek D, Martinez S, Tsai R, Boucher J, Berman JM, Teng K, Ayyaz A, Lü Y, Mbamalu G, Loganathan SK, Lee J, Zhang L, Guidos C, Wrana J, Valipour A, Roux PP, Reimand J, Jackson HW, and Schramek D
- Published
- 2023
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13. An Automation Workflow for High-Throughput Manufacturing and Analysis of Scaffold-Supported 3D Tissue Arrays.
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Cao R, Li NT, Latour S, Cadavid JL, Tan CM, Forman A, Jackson HW, and McGuigan AP
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- Humans, Workflow, Coculture Techniques, High-Throughput Screening Assays methods, Automation, Organoids, Neoplasms pathology
- Abstract
Patient-derived organoids have emerged as a useful tool to model tumour heterogeneity. Scaling these complex culture models while enabling stratified analysis of different cellular sub-populations, however, remains a challenge. One strategy to enable higher throughput organoid cultures is the scaffold-supported platform for organoid-based tissues (SPOT). SPOT allows the generation of flat, thin, and dimensionally-defined microtissues in both 96- and 384-well plate footprints that are compatible with longitudinal image-based readouts. SPOT is currently manufactured manually, however, limiting scalability. In this study, an automation approach to engineer tumour-mimetic 3D microtissues in SPOT using a liquid handler is optimized and comparable within- and between-sample variation to standard manual manufacturing is shown. Further, a liquid handler-supported cell extraction protocol to support single-cell-based end-point analysis using high-throughput flow cytometry and multiplexed cytometry by time of flight is developed. As a proof-of-value demonstration, 3D complex tissues containing different proportions of tumour and stromal cells are generated to probe the reciprocal impact of co-culture. It is also demonstrated that primary patient-derived organoids can be incorporated into the pipeline to capture patient-level tumour heterogeneity. It is envisioned that this automated 96/384-SPOT workflow will provide opportunities for future applications in high-throughput screening for novel personalized therapeutic targets., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)
- Published
- 2023
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14. An Engineered Paper-Based 3D Coculture Model of Pancreatic Cancer to Study the Impact of Tissue Architecture and Microenvironmental Gradients on Cell Phenotype.
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Cadavid JL, Latour S, Nowlan F, Co IL, Landon-Brace N, Wouters BG, Grünwald BT, Nitz M, Jackson HW, and McGuigan AP
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- Humans, Coculture Techniques, Phenotype, Tumor Microenvironment, Pancreatic Neoplasms, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal pathology
- Abstract
The spatial configuration of cells in the tumor microenvironment (TME) affects both cancer and fibroblast cell phenotypes contributing to the clinical challenge of tumor heterogeneity and therapeutic resistance. This is a particular challenge in stroma-rich pancreatic ductal adenocarcinoma (PDAC). Here, a versatile system is described to study the impact of tissue architecture on cell phenotype using PDAC as a model system. This fully human system encompassing both primary pancreatic stellate cells and primary organoid cells using the TRACER platform to allow the creation of user-defined TME architectures that have been inferred from clinical PDAC samples and are analyzed by CyTOF to characterize cells extracted from the system. High dimensional characterization using CyTOF demonstrates that tissue architecture leads to distinct hypoxia and proliferation gradients. Furthermore, phenotypic markers for both cell types are also graded in ways that cannot be explained by either hypoxia or coculture alone. This demonstrates the importance of using complex models encompassing cancer cells, stromal cells, and allowing control over architecture to explore the impact of tissue architecture on cell phenotype. It is anticipated that this model will help decipher how tissue architecture and cell interactions regulate cell phenotype and hence cellular and tissue heterogeneity., (© 2022 Wiley-VCH GmbH.)
- Published
- 2023
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15. In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.
- Author
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Dervovic D, Malik AA, Chen ELY, Narimatsu M, Adler N, Afiuni-Zadeh S, Krenbek D, Martinez S, Tsai R, Boucher J, Berman JM, Teng K, Ayyaz A, Lü Y, Mbamalu G, Loganathan SK, Lee J, Zhang L, Guidos C, Wrana J, Valipour A, Roux PP, Reimand J, Jackson HW, and Schramek D
- Subjects
- Animals, Humans, Male, Mice, Antigens, Neoplasm, Immunotherapy, Membrane Proteins genetics, T-Lymphocytes, Cytotoxic, Tumor Microenvironment, Antineoplastic Agents, Fertilins genetics, Lung Neoplasms genetics, Lung Neoplasms therapy, Serpins genetics
- Abstract
How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by Kras
G12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies., (© 2023. The Author(s).)- Published
- 2023
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16. Multiplex imaging of breast cancer lymph node metastases identifies prognostic single-cell populations independent of clinical classifiers.
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Fischer JR, Jackson HW, de Souza N, Varga Z, Schraml P, Moch H, and Bodenmiller B
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- Humans, Lymphatic Metastasis pathology, Prognosis, Lymph Nodes diagnostic imaging, Lymph Nodes pathology
- Abstract
Although breast cancer mortality is largely caused by metastasis, clinical decisions are based on analysis of the primary tumor and on lymph node involvement but not on the phenotype of disseminated cells. Here, we use multiplex imaging mass cytometry to compare single-cell phenotypes of primary breast tumors and matched lymph node metastases in 205 patients. We observe extensive phenotypic variability between primary and metastatic sites and that disseminated cell phenotypes frequently deviate from the clinical disease subtype. We identify single-cell phenotypes and spatial organizations of disseminated tumor cells that are associated with patient survival and a weaker survival association for high-risk phenotypes in the primary tumor. We show that p53 and GATA3 in lymph node metastases provide prognostic information beyond clinical classifiers and can be measured with standard methods. Molecular characterization of disseminated tumor cells is an untapped source of clinically applicable prognostic information for breast cancer., Competing Interests: Declaration of interests J.R.F. and B.B. have founded and are shareholders of Navignostics, a spin-off from University of Zurich. B.B. is a member of the board of directors and J.R.F. is the CEO. J.R.F., H.W.J., and B.B. have made a patent application related to this work, licensed to Navignostics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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17. Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer.
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Langille E, Al-Zahrani KN, Ma Z, Liang M, Uuskula-Reimand L, Espin R, Teng K, Malik A, Bergholtz H, Ghamrasni SE, Afiuni-Zadeh S, Tsai R, Alvi S, Elia A, Lü Y, Oh RH, Kozma KJ, Trcka D, Narimatsu M, Liu JC, Nguyen T, Barutcu S, Loganathan SK, Bremner R, Bader GD, Egan SE, Cescon DW, Sørlie T, Wrana JL, Jackson HW, Wilson MD, Witkiewicz AK, Knudsen ES, Pujana MA, Wahl GM, and Schramek D
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- Humans, Mice, Animals, Female, Epigenesis, Genetic, Neoplasm Recurrence, Local genetics, Cell Transformation, Neoplastic genetics, Breast Neoplasms pathology, Carcinoma, Intraductal, Noninfiltrating genetics
- Abstract
Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent "long-tail" breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology., Significance: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. This article is highlighted in the In This Issue feature, p. 2711., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
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18. Single-cell proteomics defines the cellular heterogeneity of localized prostate cancer.
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De Vargas Roditi L, Jacobs A, Rueschoff JH, Bankhead P, Chevrier S, Jackson HW, Hermanns T, Fankhauser CD, Poyet C, Chun F, Rupp NJ, Tschaebunin A, Bodenmiller B, and Wild PJ
- Subjects
- Genomics, Humans, Male, Orchiectomy, Prostate metabolism, Tumor Microenvironment genetics, Prostatic Neoplasms genetics, Proteomics methods
- Abstract
Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease., Competing Interests: P.J.W. has received consulting fees and honoraria (institutional/personal) for lectures by Bayer, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Sophia Genetics, Qiagen, and Astra Zeneca. L.D.V.R. is an employee at Monte Rosa Therapeutics. All other authors have declared no competing interests., (© 2022 The Author(s).)
- Published
- 2022
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19. Genetic perturbations go spatial.
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Teng K and Jackson HW
- Abstract
Tissue-tumor interactivity is the culmination of cell intrinsic features and their extrinsic interactions with the environment. Recently in Cell , Dhainaut and Rose et al. established a strategy to track pooled CRISPR-modified cells in vivo using protein barcodes (Pro-Codes) and measure their impact on the tumor microenvironment through multiplexed imaging and spatial transcriptomics of intact tissues.
1 ., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)- Published
- 2022
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20. Automated assignment of cell identity from single-cell multiplexed imaging and proteomic data.
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Geuenich MJ, Hou J, Lee S, Ayub S, Jackson HW, and Campbell KR
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- Cluster Analysis, Neural Networks, Computer, Proteomics
- Abstract
A major challenge in the analysis of highly multiplexed imaging data is the assignment of cells to a priori known cell types. Existing approaches typically solve this by clustering cells followed by manual annotation. However, these often require several subjective choices and cannot explicitly assign cells to an uncharacterized type. To help address these issues we present Astir, a probabilistic model to assign cells to cell types by integrating prior knowledge of marker proteins. Astir uses deep recognition neural networks for fast inference, allowing for annotations at the million-cell scale in the absence of a previously annotated reference. We apply Astir to over 2.4 million cells from suspension and imaging datasets and demonstrate its scalability, robustness to sample composition, and interpretable uncertainty estimates. We envision deployment of Astir either for a first broad cell type assignment or to accurately annotate cells that may serve as biomarkers in multiple disease contexts. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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21. Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis.
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Li L, Guturi KKN, Gautreau B, Patel PS, Saad A, Morii M, Mateo F, Palomero L, Barbour H, Gomez A, Ng D, Kotlyar M, Pastrello C, Jackson HW, Khokha R, Jurisica I, Affar EB, Raught B, Sanchez O, Alaoui-Jamali M, Pujana MA, Hakem A, and Hakem R
- Published
- 2021
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22. Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer.
- Author
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Ali HR, Jackson HW, Zanotelli VRT, Danenberg E, Fischer JR, Bardwell H, Provenzano E, Rueda OM, Chin SF, Aparicio S, Caldas C, and Bodenmiller B
- Subjects
- Ecosystem, Female, Genomics methods, Humans, Image Cytometry, Prognosis, Breast Neoplasms diagnosis
- Abstract
Genomic alterations shape cell phenotypes and the structure of tumor ecosystems in poorly defined ways. To investigate these relationships, we used imaging mass cytometry to quantify the expression of 37 proteins with subcellular spatial resolution in 483 tumors from the METABRIC cohort. Single-cell analysis revealed cell phenotypes spanning epithelial, stromal and immune types. Distinct combinations of cell phenotypes and cell-cell interactions were associated with genomic subtypes of breast cancer. Epithelial luminal cell phenotypes separated into those predominantly impacted by mutations and those affected by copy number aberrations. Several features of tumor ecosystems, including cellular neighborhoods, were linked to prognosis, illustrating their clinical relevance. In summary, systematic analysis of single-cell phenotypic and spatial correlates of genomic alterations in cancer revealed how genomes shape both the composition and architecture of breast tumor ecosystems and will enable greater understanding of the phenotypic impact of genomic alterations., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2020
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23. The single-cell pathology landscape of breast cancer.
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Jackson HW, Fischer JR, Zanotelli VRT, Ali HR, Mechera R, Soysal SD, Moch H, Muenst S, Varga Z, Weber WP, and Bodenmiller B
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- Biomarkers, Tumor analysis, Breast Neoplasms classification, Breast Neoplasms diagnosis, Humans, Kaplan-Meier Estimate, Phenotype, Proportional Hazards Models, Survival Rate, Tumor Microenvironment, Breast Neoplasms pathology, Molecular Imaging, Single-Cell Analysis
- Abstract
Single-cell analyses have revealed extensive heterogeneity between and within human tumours
1-4 , but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry5 to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.- Published
- 2020
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24. Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis.
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Li L, Guturi KKN, Gautreau B, Patel PS, Saad A, Morii M, Mateo F, Palomero L, Barbour H, Gomez A, Ng D, Kotlyar M, Pastrello C, Jackson HW, Khokha R, Jurisica I, Affar EB, Raught B, Sanchez O, Alaoui-Jamali M, Pujana MA, Hakem A, and Hakem R
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, DNA Breaks, Double-Stranded, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Mammary Glands, Animal pathology, Mammary Neoplasms, Animal genetics, Mammary Neoplasms, Animal pathology, Mice, Mice, Knockout, Neoplasm Proteins genetics, Receptor, Notch1 genetics, Ubiquitin-Protein Ligases genetics, Carcinogenesis metabolism, Mammary Glands, Animal metabolism, Mammary Neoplasms, Animal metabolism, Neoplasm Proteins metabolism, Receptor, Notch1 metabolism, Signal Transduction, Ubiquitin-Protein Ligases biosynthesis
- Abstract
The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.
- Published
- 2018
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25. Simultaneous Multiplexed Imaging of mRNA and Proteins with Subcellular Resolution in Breast Cancer Tissue Samples by Mass Cytometry.
- Author
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Schulz D, Zanotelli VRT, Fischer JR, Schapiro D, Engler S, Lun XK, Jackson HW, and Bodenmiller B
- Published
- 2018
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26. histoCAT: analysis of cell phenotypes and interactions in multiplex image cytometry data.
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Schapiro D, Jackson HW, Raghuraman S, Fischer JR, Zanotelli VRT, Schulz D, Giesen C, Catena R, Varga Z, and Bodenmiller B
- Subjects
- Algorithms, Image Interpretation, Computer-Assisted methods, User-Computer Interface, Cell Communication physiology, Flow Cytometry methods, Molecular Imaging methods, Proteome metabolism, Software, Tissue Array Analysis methods
- Abstract
Single-cell, spatially resolved omics analysis of tissues is poised to transform biomedical research and clinical practice. We have developed an open-source, computational histology topography cytometry analysis toolbox (histoCAT) to enable interactive, quantitative, and comprehensive exploration of individual cell phenotypes, cell-cell interactions, microenvironments, and morphological structures within intact tissues. We highlight the unique abilities of histoCAT through analysis of highly multiplexed mass cytometry images of human breast cancer tissues.
- Published
- 2017
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27. TIMPs: versatile extracellular regulators in cancer.
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Jackson HW, Defamie V, Waterhouse P, and Khokha R
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- Biomarkers, Tumor metabolism, Biomarkers, Tumor physiology, Humans, Proteolysis, Signal Transduction, Tissue Inhibitor of Metalloproteinases physiology, Tumor Microenvironment physiology, Neoplasms metabolism, Neoplasms physiopathology, Tissue Inhibitor of Metalloproteinases metabolism
- Abstract
A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.
- Published
- 2017
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28. Tumor suppression by stromal TIMPs.
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Shimoda M, Jackson HW, and Khokha R
- Abstract
The tumor stroma has the capacity to drive cancer progression, although the mechanisms governing these effects are incompletely understood. Recently, we reported that deletion of tissue inhibitor of metalloproteinases (Timps) in fibroblasts unleashes the function of cancer-associated fibroblasts and identifies a novel mode of stromal-tumor communication that activates key oncogenic pathways invoving Notch and ras homolog gene family, member A (RhoA) via stromal exosomes.
- Published
- 2016
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29. RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1.
- Author
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Joshi PA, Waterhouse PD, Kannan N, Narala S, Fang H, Di Grappa MA, Jackson HW, Penninger JM, Eaves C, and Khokha R
- Subjects
- Animals, Cell Proliferation genetics, Female, Humans, Mammary Glands, Animal growth & development, Mice, Receptor Activator of Nuclear Factor-kappa B antagonists & inhibitors, Thrombospondins biosynthesis, Wnt Signaling Pathway genetics, Mammary Glands, Animal metabolism, Receptor Activator of Nuclear Factor-kappa B genetics, Stem Cells cytology, Thrombospondins genetics
- Abstract
Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
30. Timp3 deficient mice show resistance to developing breast cancer.
- Author
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Jackson HW, Hojilla CV, Weiss A, Sanchez OH, Wood GA, and Khokha R
- Subjects
- Animals, Cell Transformation, Neoplastic pathology, Female, Male, Mammary Glands, Animal pathology, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental pathology, Mice, Mice, Inbred C57BL, Signal Transduction genetics, Tumor Necrosis Factor-alpha genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Transformation, Neoplastic genetics, Tissue Inhibitor of Metalloproteinase-3 deficiency, Tissue Inhibitor of Metalloproteinase-3 genetics
- Abstract
Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-⁄- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-⁄- mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.
- Published
- 2015
- Full Text
- View/download PDF
31. A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland.
- Author
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Shiah YJ, Tharmapalan P, Casey AE, Joshi PA, McKee TD, Jackson HW, Beristain AG, Chan-Seng-Yue MA, Bader GD, Lydon JP, Waterhouse PD, Boutros PC, and Khokha R
- Abstract
Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24
+ CD49fhi ) and luminal (CD24+ CD49flo ) subsets. This is accompanied by a marked reduction in CD49b+ SCA-1- luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2015
- Full Text
- View/download PDF
32. Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice.
- Author
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Jackson HW, Waterhouse P, Sinha A, Kislinger T, Berman HK, and Khokha R
- Subjects
- Age Factors, Aging metabolism, Animals, Cell Differentiation, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Female, Gene Expression Regulation, Developmental, Mammary Glands, Animal growth & development, Mammary Glands, Animal metabolism, Mice, Mice, Knockout, Mitosis, Receptors, Notch genetics, Receptors, Notch metabolism, Risk Factors, Signal Transduction, Spindle Apparatus metabolism, Spindle Apparatus pathology, Stem Cells metabolism, Tissue Inhibitor of Metalloproteinase-1 deficiency, Tissue Inhibitor of Metalloproteinase-3 deficiency, Aging genetics, Cell Proliferation genetics, Mammary Glands, Animal cytology, Stem Cells cytology, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-3 genetics
- Abstract
Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cell-extrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11-fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp1/Timp3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model.
- Published
- 2015
- Full Text
- View/download PDF
33. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.
- Author
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Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T, and Khokha R
- Subjects
- ADAM Proteins metabolism, ADAM10 Protein, Amyloid Precursor Protein Secretases metabolism, Animals, Cell Line, Tumor, Cell Movement, Exosomes physiology, Female, Fibroblasts pathology, Humans, Lung Neoplasms enzymology, Mammary Neoplasms, Experimental enzymology, Membrane Proteins metabolism, Metalloendopeptidases metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Transplantation, Phenotype, Signal Transduction, Tissue Inhibitor of Metalloproteinases deficiency, Tumor Burden, Fibroblasts metabolism, Lung Neoplasms secondary, Mammary Neoplasms, Experimental pathology, Tissue Inhibitor of Metalloproteinases genetics
- Abstract
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.
- Published
- 2014
- Full Text
- View/download PDF
34. TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence.
- Author
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Hojilla CV, Jackson HW, and Khokha R
- Subjects
- Adherens Junctions drug effects, Adherens Junctions metabolism, Adipogenesis drug effects, Animals, Cadherins metabolism, Caspase 3 metabolism, Cell Survival drug effects, Enzyme Activation drug effects, Epithelial Cells drug effects, Epithelial Cells enzymology, Female, Humans, Inflammation pathology, Lymphocytes drug effects, Mammary Glands, Animal enzymology, Mammary Glands, Animal growth & development, Mammary Glands, Animal immunology, Mice, Mice, Inbred C57BL, Models, Biological, Recombinant Proteins pharmacology, Signal Transduction drug effects, Tissue Inhibitor of Metalloproteinase-3 deficiency, Apoptosis drug effects, Epithelial Cells immunology, Epithelial Cells pathology, Lymphocytes immunology, Mammary Glands, Animal pathology, Tissue Inhibitor of Metalloproteinase-3 metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Post-lactation mammary involution is a homeostatic process requiring epithelial apoptosis and clearance. Given that the deficiency of the extracellular metalloproteinase inhibitor TIMP3 impacts epithelial apoptosis and heightens inflammatory response, we investigated whether TIMP3 regulates these distinct processes during the phases of mammary gland involution in the mouse. Here we show that TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation and onset of mitochondrial apoptosis. This accelerated first phase of involution includes faster loss of initiating signals (STAT3 activation; TGFβ3) concurrent with immediate luminal deconstruction through E-cadherin fragmentation. Epithelial apoptosis is followed by accelerated adipogenesis and a greater macrophage and T-cell infiltration in Timp3(-/-) involuting glands. Crossing in Tnf deficiency abrogates caspase 3 activation, but heightens macrophage and T-cell influx into Timp3(-/-) glands. The data indicate that TIMP3 differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution. An understanding of the molecular factors and wound healing microenvironment of the postpartum mammary gland may have implications for understanding pregnancy-associated breast cancer risk.
- Published
- 2011
- Full Text
- View/download PDF
35. Progesterone induces adult mammary stem cell expansion.
- Author
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Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, Stingl J, Waterhouse PD, and Khokha R
- Subjects
- Animals, Cell Count, Cell Division drug effects, Cell Transformation, Neoplastic, Estrogens pharmacology, Estrous Cycle blood, Estrous Cycle physiology, Female, Homeostasis drug effects, Integrin alpha6 metabolism, Mice, Ovariectomy, Paracrine Communication drug effects, Progesterone blood, Progesterone metabolism, RANK Ligand metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Stem Cell Niche cytology, Stem Cell Niche drug effects, Stem Cell Niche metabolism, Stem Cells metabolism, Wnt Proteins metabolism, Wnt4 Protein, Aging physiology, Mammary Glands, Animal cytology, Progesterone pharmacology, Stem Cells cytology, Stem Cells drug effects
- Abstract
Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.
- Published
- 2010
- Full Text
- View/download PDF
36. Third-sound propagation in thick films of superfluid 4He.
- Author
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Jackson HW and Mason PV
- Published
- 1990
- Full Text
- View/download PDF
37. HYGIENIC GUIDE SERIES. ALLYL ALCOHOL (2-PROPEN-1-OL).
- Author
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JACKSON HW, HUSTED FB, and LAROCQUE WR
- Subjects
- Humans, Propanols
- Published
- 1963
- Full Text
- View/download PDF
38. HYGIENIC GUIDE SERIES. ALLYL CHLORIDE (3-CHLORO-1-PROPENE).
- Author
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JACKSON HW, HUSTED FB, and LAROCQUE WR
- Subjects
- Alkenes, Humans, Allyl Compounds, Chlorides
- Published
- 1963
- Full Text
- View/download PDF
39. A COMPACT EXHAUST VENTILATION TRAINING AID.
- Author
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JACKSON HW, HUSTED FB, and LAROCQUE WR
- Subjects
- Humans, Air Pollution, Equipment and Supplies, Occupational Medicine, Respiration, Vehicle Emissions, Ventilation
- Published
- 1963
- Full Text
- View/download PDF
40. ENURESIS SUCCESSFULLY TREATED WITH SHORT-TERM PSYCHOTHERAPY. A CASE REPORT.
- Author
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SILVERMAN MA and JACKSON HW
- Subjects
- Humans, Enuresis, Military Personnel, Military Psychiatry, Nocturnal Enuresis, Psychiatry, Psychotherapy, Psychotherapy, Brief
- Published
- 1964
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