DOCSLIB.ORG

A Novel Role for Cadherin-11

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Role for Cadherin-11 Mechanobiology of Cardiac Disease and Fibrosis: a Novel Role for Cadherin-11 By Alison Koelle Schroer Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biomedical Engineering December, 2016 Nashville, Tennessee Approved: W. David Merryman, Ph.D. John Wikswo, Ph.D. Michael Miga, Ph.D. Jeffrey Davidson, Ph.D. Antonis Hatzopoulos, Ph.D. Copyright © 2016 by Alison K Schroer All Rights Reserved ii ACKNOWLEDGEMENTS The heart has its reasons, of which reason knows nothing - Pascal I must acknowledge my coauthors on the manuscripts which have been adapted and included in this dissertation. First and foremost, my advisor Dave Merryman. Also Larisa Rhyzhova, Cyndi Clark, Hind Lal, Qinkun Zhang, Tom Force, John Wikswo, Veniamin Sidorov, Matthew Shotwell, Annabelle Manalo, and David Bader. I would also acknowledge Josh Bender and Claire Lafferty, undergraduate research assistants who assisted in the collection of some of the data included in this work. I would also like to acknowledge Meghan Bowler, Mark Vander Roest, Caleb Snider, Allison Price, and Jeffrey Davidson for their editorial comments on the work included in this dissertation. I would like to acknowledge my funding sources, especially the NSF and the AHA. Also, the ever wonderful Merryman Lab, members both past and present, who have been my comrades and friends throughout the last five years. Finally, I must acknowledge my family, my friends, and my God, without whom I never could have done all this. Keep your heart with all vigilance, for from it flow the springs of life. - Proverbs 4:23 iii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES ............................................................................................................ vi LIST OF FIGURES ......................................................................................................... vii CHAPTER 1. Introduction and Motivation ......................................................................................... 1 2. Background: Myocardial Development and Disease ................................................... 8 Mechanobiology of cardiac development.................................................................. 8 Cellular players in fibrotic cardiac disease, parallels with valve disease ................ 10 Etiology of cardiac fibrotic disease ......................................................................... 15 3. Background: Fibroblast Mechanobiology .................................................................. 21 Myofibroblast differentiation in response to mechanical stress ............................... 21 Integrins sense mechanical signals from the ECM ................................................. 28 Cadherins sense intercellular forces ....................................................................... 33 4. Aim 1: Elucidating Mechanosensitive Signaling Crosstalk in Fibroblasts .................. 39 Introduction ............................................................................................................. 39 Methods ................................................................................................................. 45 Results .................................................................................................................... 47 Discussion ............................................................................................................. 56 5. Aim 2: Cadherin-11 Exacerbates Tissue Remodeling after Myocardial Infarction ..... 62 Introduction ............................................................................................................. 62 Methods ................................................................................................................. 63 Results .................................................................................................................... 71 Discussion .............................................................................................................. 93 iv 6. Aim 3: Quantifying Cardiomyocyte Mechanics ........................................................ 105 Introduction to cardiomyocytes and motivation for study ...................................... 105 CENP-F mutation alters cardiac cell structure and mechanics ............................. 106 Introduction to engineered cardiac tissue constructs ............................................ 113 Methods of I-wire development and analysis ........................................................ 116 Results of I-wire analysis ...................................................................................... 123 Disscussion .......................................................................................................... 131 7. Impact and Future Directions .................................................................................. 137 Summary and impact of results ............................................................................ 137 Future directions ................................................................................................... 144 APPENDIX A. Model of Myofibroblast Differentiation ..................................................................... 148 B. Model Derivation for I-wire ...................................................................................... 166 REFERENCES ............................................................................................................ 180 v LIST OF TABLES Table Page 1.1 Vocabulary and Abbreviations ................................................................................... 7 3.1 Summary of integrin isoform expression in normal function and disease ................ 27 3.2 Summary of cadherin isoform expression in normal function and disease .............. 27 5.1 qPCR primers .......................................................................................................... 70 6.1 Model variables ..................................................................................................... 120 6.2 Passive mechanic metrics for control and isoproterenol-treated ECTCs ............... 124 vi LIST OF FIGURES Figure Page 1.1 Graphical overview of dissertation topic and aims..................................................... 5 2.1 Interplay between ECM stiffness and fibroblast phenotypes ................................... 10 2.2 Relevance of adhesion mechanobiology to fibrotic heart disease ........................... 14 2.3 Schematic of the stages in healing after myocardial infarction ................................ 19 3.1 Mechano-sensitive mechanisms of myofibroblast differentiation ............................. 23 3.2 Crosstalk between growth factor and adhesion protein signaling ............................ 32 4.1 Src and p38 are necessary for TGF-β1 induced myofibroblast differentiation ......... 42 4.2 Relevant signaling network ..................................................................................... 43 4.3 α-SMA is oppositely regulated by TGF-β1 and FGF2 through focal adhesion proteins and p38 and ERK dependent mechanisms ..................................................... 49 4.4 Different dynamic activation profiles for activation of ERK and p38 ........................ 51 4.5 α-SMA and cadherin-11 are not necessarily coexpressed ...................................... 53 4.6 α-SMA and cadherin-11 are sensitive to stiffness and the presence of FAK ........... 55 4.7 Expression of myofibroblast markers after treatment with TGF-β1 and FGF2 with GSK-3β inhibition .......................................................................................................... 56 5.1 Cadherin-11 is expressed after myocardial infarction .............................................. 73 5.2 Cadherin-11 null hearts respond differently after MI................................................ 75 5.3 Cadherin-11 blocking antibody treatment improves outcomes after MI ................... 77 5.4 SYN0012 reduces infarct remodeling and myofibroblast differentiation. ................. 79 5.5 SYN0012 effect on CF contractility .......................................................................... 80 5.6 Reduction of IL-6 observed 3 days post-MI in vivo with SYN0012 treatment .......... 82 vii 5.7 Reduction of F4/80 observed 3 days post-MI in vivo with SYN0012 treatment ....... 82 5.8 Transcriptional changes of inflammatory proteins after MI ...................................... 84 5.9 Transcriptional changes of pro-fibrotic proteins after MI .......................................... 85 5.10 Transcriptional changes of pro-angiogenic proteins after MI ................................. 87 5.11 Co-culture of macrophages and fibroblasts increase expression of IL-6 and MMP13 .......................................................................................................................... 89 5.12 Co-culture effects on other aspects of inflammatory/remodeling cascade ............ 90 5.13 Transcriptional changes of markers of macrophage polarization .......................... 92 5.14 Proposed cellular mechanisms of cadherin-11 in macrophages and fibroblasts . 101 5.15 Summary of results ............................................................................................. 103 6.1 Quantification of sarcomere length .......................................................................
Load more

Recommended publications
  • Propranolol-Mediated Attenuation of MMP-9 Excretion in Infants with Hemangiomas
    Supplementary Online Content Thaivalappil S, Bauman N, Saieg A, Movius E, Brown KJ, Preciado D. Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas. JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2013.4773 eTable. List of All of the Proteins Identified by Proteomics This supplementary material has been provided by the authors to give readers additional information about their work. © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable. List of All of the Proteins Identified by Proteomics Protein Name Prop 12 mo/4 Pred 12 mo/4 Δ Prop to Pred mo mo Myeloperoxidase OS=Homo sapiens GN=MPO 26.00 143.00 ‐117.00 Lactotransferrin OS=Homo sapiens GN=LTF 114.00 205.50 ‐91.50 Matrix metalloproteinase‐9 OS=Homo sapiens GN=MMP9 5.00 36.00 ‐31.00 Neutrophil elastase OS=Homo sapiens GN=ELANE 24.00 48.00 ‐24.00 Bleomycin hydrolase OS=Homo sapiens GN=BLMH 3.00 25.00 ‐22.00 CAP7_HUMAN Azurocidin OS=Homo sapiens GN=AZU1 PE=1 SV=3 4.00 26.00 ‐22.00 S10A8_HUMAN Protein S100‐A8 OS=Homo sapiens GN=S100A8 PE=1 14.67 30.50 ‐15.83 SV=1 IL1F9_HUMAN Interleukin‐1 family member 9 OS=Homo sapiens 1.00 15.00 ‐14.00 GN=IL1F9 PE=1 SV=1 MUC5B_HUMAN Mucin‐5B OS=Homo sapiens GN=MUC5B PE=1 SV=3 2.00 14.00 ‐12.00 MUC4_HUMAN Mucin‐4 OS=Homo sapiens GN=MUC4 PE=1 SV=3 1.00 12.00 ‐11.00 HRG_HUMAN Histidine‐rich glycoprotein OS=Homo sapiens GN=HRG 1.00 12.00 ‐11.00 PE=1 SV=1 TKT_HUMAN Transketolase OS=Homo sapiens GN=TKT PE=1 SV=3 17.00 28.00 ‐11.00 CATG_HUMAN Cathepsin G OS=Homo
    [Show full text]
  • Melanoma in the Eyes of Mechanobiology
    fcell-08-00054 February 11, 2020 Time: 16:43 # 1 REVIEW published: 11 February 2020 doi: 10.3389/fcell.2020.00054 Melanoma in the Eyes of Mechanobiology M. Manuela Brás1,2,3, Manfred Radmacher4*, Susana R. Sousa1,2,5 and Pedro L. Granja1,2,3† 1 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal, 2 Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal, 3 Faculdade de Engenharia, Universidade do Porto, Porto, Portugal, 4 Institute for Biophysics, University of Bremen, Bremen, Germany, 5 Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto, Portugal Skin is the largest organ of the human body with several important functions that can be impaired by injury, genetic or chronic diseases. Among all skin diseases, melanoma is one of the most severe, which can lead to death, due to metastization. Mechanotransduction has a crucial role for motility, invasion, adhesion and metastization processes, since it deals with the response of cells to physical forces. Signaling Edited by: pathways are important to understand how physical cues produced or mediated Shamik Sen, by the Extracellular Matrix (ECM), affect healthy and tumor cells. During these Indian Institute of Technology Bombay, India processes, several molecules in the nucleus and cytoplasm are activated. Melanocytes, Reviewed by: keratinocytes, fibroblasts and the ECM, play a crucial role in melanoma formation. This Zhizhan Gu, manuscript will address the synergy among melanocytes, keratinocytes, fibroblasts cells Dana-Farber Cancer Institute, United States and the ECM considering their mechanical contribution and relevance in this disease. Takashi Kato, Mechanical properties of melanoma cells can also be influenced by pigmentation, Johns Hopkins University, which can be associated with changes in stiffness.
    [Show full text]
  • Quantitative Methodologies to Dissect Immune Cell Mechanobiology
    cells Review Quantitative Methodologies to Dissect Immune Cell Mechanobiology Veronika Pfannenstill 1 , Aurélien Barbotin 1 , Huw Colin-York 1,* and Marco Fritzsche 1,2,* 1 Kennedy Institute for Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK; [email protected] (V.P.); [email protected] (A.B.) 2 Rosalind Franklin Institute, Harwell Campus, Didcot OX11 0FA, UK * Correspondence: [email protected] (H.C.-Y.); [email protected] (M.F.) Abstract: Mechanobiology seeks to understand how cells integrate their biomechanics into their function and behavior. Unravelling the mechanisms underlying these mechanobiological processes is particularly important for immune cells in the context of the dynamic and complex tissue microen- vironment. However, it remains largely unknown how cellular mechanical force generation and mechanical properties are regulated and integrated by immune cells, primarily due to a profound lack of technologies with sufficient sensitivity to quantify immune cell mechanics. In this review, we discuss the biological significance of mechanics for immune cells across length and time scales, and highlight several experimental methodologies for quantifying the mechanics of immune cells. Finally, we discuss the importance of quantifying the appropriate mechanical readout to accelerate insights into the mechanobiology of the immune response. Keywords: mechanobiology; biomechanics; force; immune response; quantitative technology Citation: Pfannenstill, V.; Barbotin, A.; Colin-York, H.; Fritzsche, M. Quantitative Methodologies to Dissect 1. Introduction Immune Cell Mechanobiology. Cells The development of novel quantitative technologies and their application to out- 2021, 10, 851. https://doi.org/ standing scientific problems has often paved the way towards ground-breaking biological 10.3390/cells10040851 findings.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Learning from Cadherin Structures and Sequences: Affinity Determinants and Protein Architecture
    Learning from cadherin structures and sequences: affinity determinants and protein architecture Klára Fels ıvályi Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Klara Felsovalyi All rights reserved ABSTRACT Learning from cadherin structures and sequences: affinity determinants and protein architecture Klara Felsovalyi Cadherins are a family of cell-surface proteins mediating adhesion that are important in development and maintenance of tissues. The family is defined by the repeating cadherin domain (EC) in their extracellular region, but they are diverse in terms of protein size, architecture and cellular function. The best-understood subfamily is the type I classical cadherins, which are found in vertebrates and have five EC domains. Among the five different type I classical cadherins, the binding interactions are highly specific in their homo- and heterophilic binding affinities, though their sequences are very similar. As previously shown, E- and N-cadherins, two prototypic members of the subfamily, differ in their homophilic K D by about an order of magnitude, while their heterophilic affinity is intermediate. To examine the source of the binding affinity differences among type I cadherins, we used crystal structures, analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and electron paramagnetic resonance (EPR) studies. Phylogenetic analysis and binding affinity behavior show that the type I cadherins can be further divided into two subgroups, with E- and N-cadherin representing each. In addition to the affinity differences in their wild-type binding through the strand-swapped interface, a second interface also shows an affinity difference between E- and N-cadherin.
    [Show full text]
  • Mechanobiology of Migrating Cells from Basic Science to the Clinic
    A COST Action CA15214 (EuroCellNet) Working Group Meeting Mechanobiology of Migrating Cells From Basic Science to the Clinic 1st – 2nd April 2019 Venue Department of Physics Rua Larga, University of Coimbra 2 Coimbra 2019 Monday, 1st April 09.45 - 10.00 WELCOME AND INTRODUCTION Keynote Speaker 10.00 – 10.40 M. Ángela Nieto, Instituto de Neurociencias (CSIC-UMH), Alicante, Spain “Epithelial plasticity in health and disease (the INs and OUTs of the EMT)” ECM and Cell Migration Session Chair: Nuno Saraiva 10.40 – 11.00 Florence Janody, University of Porto, Portugal “Computational modelling and experimental approaches identify a role of ECM stiffening in Src- induces EMT” 11.00 - 11.20 Juan Carlos Rodríguez-Manzaneque, GENYO, Granada, Spain “Relevance of ECM proteolytic remodelling for cell invasion and migration” 11.20 - 11.40 Rui Travasso, University of Coimbra, Portugal “Mathematical modelling of migrating cells and angiogenesis” 11.40 - 12.00 María José Oliveira, University of Porto, Portugal “Decellularized human colorectal cancer matrices as a tumor microenvironment biomimetic model” 12.00 – 14.00 Lunch Justiça e Paz, Couraça de Lisboa, 30 Keynote Speaker 14.00 - 14.40 Lino Ferreira, University of Coimbra, Portugal “Mechanical forces in vascular cell maturation and disease” 4 Coimbra 2019 Mechanotransduction and Cytoskeleton Session Chair: Ana Fernandes 14.40 - 15.00 Mirjana Liovic, Medical Center for Molecular Biology, Institute for Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia “Cytoskeletal mutations
    [Show full text]
  • Integrative Epigenomic and Genomic Analysis of Malignant Pheochromocytoma
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 42, No. 7, 484-502, July 2010 Integrative epigenomic and genomic analysis of malignant pheochromocytoma Johanna Sandgren1,2* Robin Andersson3*, pression examination in a malignant pheochromocy- Alvaro Rada-Iglesias3, Stefan Enroth3, toma sample. The integrated analysis of the tumor ex- Goran̈ Akerstro̊ m̈ 1, Jan P. Dumanski2, pression levels, in relation to normal adrenal medulla, Jan Komorowski3,4, Gunnar Westin1 and indicated that either histone modifications or chromo- somal alterations, or both, have great impact on the ex- Claes Wadelius2,5 pression of a substantial fraction of the genes in the in- vestigated sample. Candidate tumor suppressor 1Department of Surgical Sciences genes identified with decreased expression, a Uppsala University, Uppsala University Hospital H3K27me3 mark and/or in regions of deletion were for SE-75185 Uppsala, Sweden 2 instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, Department of Genetics and Pathology Rudbeck Laboratory, Uppsala University PTPRE and CDH11. More genes were found with in- SE-75185 Uppsala, Sweden creased expression, a H3K4me3 mark, and/or in re- 3The Linnaeus Centre for Bioinformatics gions of gain. Potential oncogenes detected among Uppsala University those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, SE-751 24 Uppsala, Sweden IGF2, and the H3K27 trimethylase gene EZH2. Our ap- 4Interdisciplinary Centre for Mathematical and proach to associate histone methylations and DNA Computational Modelling copy number changes to gene expression revealed ap- Warsaw University parent impact on global gene transcription, and en- PL-02-106 Warszawa, Poland abled the identification of candidate tumor genes for 5Corresponding author: Tel, 46-18-471-40-76; further exploration.
    [Show full text]
  • Cadherin-11 Mediates Cancer Hijacking Fibroblasts
    bioRxiv preprint doi: https://doi.org/10.1101/729491; this version posted August 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts Weirong Kang1Ϯ, Yibo Fan1Ϯ, Yinxiao Du1Ϯ, Elina A. Tonkova2, Yi-Hsin Hsu3, Kel Vin Tan4, Stephanie Alexander5, Bin Sheng Wong6, Haocheng Yang1, Jingyuan Luo1, Kuo Yao1, Jiayao Yang1, Xin Hu7, Tingting Liu8, Yu Gan8, Jian Zhang9, Jean J. Zhao10,11, Konstantinos Konstantopoulos6, Peter Friedl5, Pek Lan Khong4, Aiping Lu1, Mien-Chie Hung3,12, Michael B. Brenner2, Jeffrey E. Segall13, Zhizhan Gu1,2,6,10,13,# 1Centre for Cancer and Inflammation Research, Institute of Integrated Bioinformedicine and Translational Science, and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China 2Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 3Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA 4Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China 5Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; David H. Koch Center for Applied Research of Genitourinary Cancers, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston,
    [Show full text]
  • Integrated Micro/Nanoengineered Functional Biomaterials for Cell Mechanics and Mechanobiology: REVIEW a Materials Perspective
    www.advmat.de www.MaterialsViews.com Integrated Micro/Nanoengineered Functional Biomaterials for Cell Mechanics and Mechanobiology: REVIEW A Materials Perspective Yue Shao and Jianping Fu * which actively signals to cells to regulate The rapid development of micro/nanoengineered functional biomaterials in their fate and function. The microenviron- the last two decades has empowered materials scientists and bioengineers mental factors, including cell-cell inter- to precisely control different aspects of the in vitro cell microenvironment. actions, soluble factors such as oxygen tension and growth factors, and adhesive Following a philosophy of reductionism, many studies using synthetic and biophysical interactions between functional biomaterials have revealed instructive roles of individual extra- cells and extracellular matrix (ECM), are cellular biophysical and biochemical cues in regulating cellular behaviors. all important for regulation of cellular Development of integrated micro/nanoengineered functional biomaterials behaviors. Cells and the surrounding to study complex and emergent biological phenomena has also thrived microenvironment can also dynamically infl uence each other during normal devel- rapidly in recent years, revealing adaptive and integrated cellular behaviors opment, tissue homeostasis and repair, closely relevant to human physiological and pathological conditions. Working and progression of diseases through their at the interface between materials science and engineering, biology, and reciprocal biochemical and biophysical medicine, we are now at the beginning of a great exploration using micro/ interactions. [ 1–6 ] Thus, a detailed appre- nanoengineered functional biomaterials for both fundamental biology study hension and understanding of cell-micro- and clinical and biomedical applications such as regenerative medicine and environment interactions is critical for both advancing basic biology knowledge drug screening.
    [Show full text]
  • Modeling the Mechanobiology of Cancer Cell Migration Using 3D Biomimetic Hydrogels
    gels Review Modeling the Mechanobiology of Cancer Cell Migration Using 3D Biomimetic Hydrogels Xabier Morales †, Iván Cortés-Domínguez † and Carlos Ortiz-de-Solorzano * IDISNA, Ciberonc and Solid Tumors and Biomarkers Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; [email protected] (X.M.); [email protected] (I.C.-D.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Understanding how cancer cells migrate, and how this migration is affected by the me- chanical and chemical composition of the extracellular matrix (ECM) is critical to investigate and possibly interfere with the metastatic process, which is responsible for most cancer-related deaths. In this article we review the state of the art about the use of hydrogel-based three-dimensional (3D) scaffolds as artificial platforms to model the mechanobiology of cancer cell migration. We start by briefly reviewing the concept and composition of the extracellular matrix (ECM) and the materials commonly used to recreate the cancerous ECM. Then we summarize the most relevant knowledge about the mechanobiology of cancer cell migration that has been obtained using 3D hydrogel scaf- folds, and relate those discoveries to what has been observed in the clinical management of solid tumors. Finally, we review some recent methodological developments, specifically the use of novel bioprinting techniques and microfluidics to create realistic hydrogel-based models of the cancer ECM, and some of their applications in the context of the study of cancer cell migration. Keywords: hydrogel; collagen; Matrigel; extracellular matrix; mechanobiology; amoeboid-mesenchymal transition; cancer; cell migration; microfluidic devices; bioprinting Citation: Morales, X.; Cortés-Domínguez, I.; Ortiz-de-Solorzano, C.
    [Show full text]
  • Minimal 16Q Genomic Loss Implicates Cadherin-11 in Retinoblastoma
    Minimal 16q Genomic Loss Implicates Cadherin-11 in Retinoblastoma Mellone N. Marchong,1,2 Danian Chen,1,6 Timothy W. Corson,1,3 Cheong Lee,1 Maria Harmandayan,1 Ella Bowles,1 Ning Chen,5 and Brenda L. Gallie1,2,3,4,5 1Divisions of Cancer Informatics and Cellular and Molecular Biology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; Departments of 2Medical Biophysics, 3Molecular and Medical Genetics, and 4Ophthalmology, University of Toronto, Toronto, Ontario, Canada; 5Retinoblastoma Solutions, Toronto, Ontario, Canada; and 6Department of Ophthalmology, West China Hospital, Faculty of Medicine, Sichuan University, Chengdu, People’s Republic of China Abstract compared with normal adult human retina. Our analyses Retinoblastoma is initiated by loss of both RB1 alleles. implicate CDH11, but not CDH13, as a potential tumor Previous studies have shown that retinoblastoma suppressor gene in retinoblastoma. (Mol Cancer Res tumors also show further genomic gains and losses. We 2004;2(9):495–503) now define a 2.62 Mbp minimal region of genomic loss of chromosome 16q22, which is likely to contain tumor suppressor gene(s), in 76 retinoblastoma tumors, using Introduction loss of heterozygosity (30 of 76 tumors) and quantitative Retinoblastoma is the most common intraocular tumor in multiplex PCR (71 of 76 tumors). The sequence-tagged children. Mutations of both alleles (M1 and M2) of the RB1 site WI-5835 within intron 2 of the cadherin-11 (CDH11) gene at chromosome 13q14 are necessary (1) for retinoblastoma gene showed the highest frequency of loss (54%, 22 of tumor initiation but not sufficient for malignant transformation 41 samples tested).
    [Show full text]
  • Cell Adhesion Molecules in Normal Skin and Melanoma
    biomolecules Review Cell Adhesion Molecules in Normal Skin and Melanoma Cian D’Arcy and Christina Kiel * Systems Biology Ireland & UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland; [email protected] * Correspondence: [email protected]; Tel.: +353-1-716-6344 Abstract: Cell adhesion molecules (CAMs) of the cadherin, integrin, immunoglobulin, and selectin protein families are indispensable for the formation and maintenance of multicellular tissues, espe- cially epithelia. In the epidermis, they are involved in cell–cell contacts and in cellular interactions with the extracellular matrix (ECM), thereby contributing to the structural integrity and barrier for- mation of the skin. Bulk and single cell RNA sequencing data show that >170 CAMs are expressed in the healthy human skin, with high expression levels in melanocytes, keratinocytes, endothelial, and smooth muscle cells. Alterations in expression levels of CAMs are involved in melanoma propagation, interaction with the microenvironment, and metastasis. Recent mechanistic analyses together with protein and gene expression data provide a better picture of the role of CAMs in the context of skin physiology and melanoma. Here, we review progress in the field and discuss molecular mechanisms in light of gene expression profiles, including recent single cell RNA expression information. We highlight key adhesion molecules in melanoma, which can guide the identification of pathways and Citation: D’Arcy, C.; Kiel, C. Cell strategies for novel anti-melanoma therapies. Adhesion Molecules in Normal Skin and Melanoma. Biomolecules 2021, 11, Keywords: cadherins; GTEx consortium; Human Protein Atlas; integrins; melanocytes; single cell 1213. https://doi.org/10.3390/ RNA sequencing; selectins; tumour microenvironment biom11081213 Academic Editor: Sang-Han Lee 1.
    [Show full text]