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Title: A Systems Perspective of Heterocellular Signaling

Abstract

Signal exchange between different cell types is essential for development and function of multicellular organisms, and its dysregulation is causal in many diseases. Unfortunately, most cell-signaling work has employed single cell types grown under conditions unrelated to their native context. Recent technical developments have started to provide the tools needed to follow signaling between multiple cell types, but gaps in the information they provide have limited their usefulness in building realistic models of heterocellular signaling. Currently, only targeted assays have the necessary sensitivity, selectivity and spatial resolution to usefully probe heterocellular signaling processes, but these are best used to test specific, mechanistic models. Decades of systems biology research with monocultures has provided a solid foundation for building models of heterocellular signaling, but current models lack a realistic description of regulated proteolysis and the feedback processes triggered within and between cells. Identification and understanding of key regulatory processes in the extracellular environment and of recursive signaling patterns between cells will be essential to building predictive models of heterocellular systems.

Authors:
;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1490209
Report Number(s):
PNNL-SA-135065
Journal ID: ISSN 0071-1365
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Essays In Biochemistry
Additional Journal Information:
Journal Volume: 62; Journal Issue: 4; Journal ID: ISSN 0071-1365
Country of Publication:
United States
Language:
English
Subject:
systems biology, EGFR, heterocellular, Wound healing, Modeling & Simulation

Citation Formats

Wells, Alan, and Wiley, H.  Steven. A Systems Perspective of Heterocellular Signaling. United States: N. p., 2018. Web. doi:10.1042/EBC20180015.
Wells, Alan, & Wiley, H.  Steven. A Systems Perspective of Heterocellular Signaling. United States. doi:10.1042/EBC20180015.
Wells, Alan, and Wiley, H.  Steven. Thu . "A Systems Perspective of Heterocellular Signaling". United States. doi:10.1042/EBC20180015.
@article{osti_1490209,
title = {A Systems Perspective of Heterocellular Signaling},
author = {Wells, Alan and Wiley, H.  Steven},
abstractNote = {Signal exchange between different cell types is essential for development and function of multicellular organisms, and its dysregulation is causal in many diseases. Unfortunately, most cell-signaling work has employed single cell types grown under conditions unrelated to their native context. Recent technical developments have started to provide the tools needed to follow signaling between multiple cell types, but gaps in the information they provide have limited their usefulness in building realistic models of heterocellular signaling. Currently, only targeted assays have the necessary sensitivity, selectivity and spatial resolution to usefully probe heterocellular signaling processes, but these are best used to test specific, mechanistic models. Decades of systems biology research with monocultures has provided a solid foundation for building models of heterocellular signaling, but current models lack a realistic description of regulated proteolysis and the feedback processes triggered within and between cells. Identification and understanding of key regulatory processes in the extracellular environment and of recursive signaling patterns between cells will be essential to building predictive models of heterocellular systems.},
doi = {10.1042/EBC20180015},
journal = {Essays In Biochemistry},
issn = {0071-1365},
number = 4,
volume = 62,
place = {United States},
year = {2018},
month = {8}
}

Works referenced in this record:

Differential signaling and regulation of apical vs. basolateral EGFR in polarized epithelial cells
journal, December 1998


Pericytes: A newly recognized player in wound healing: Pericytes in wound healing
journal, March 2016

  • Bodnar, Richard J.; Satish, Latha; Yates, Cecelia C.
  • Wound Repair and Regeneration, Vol. 24, Issue 2
  • DOI: 10.1111/wrr.12415

One hundred years of hormones
journal, June 2005


IGF binding proteins and their functions
journal, August 1993


Influence of node abundance on signaling network state and dynamics analyzed by mass cytometry
journal, January 2017

  • Lun, Xiao-Kang; Zanotelli, Vito R. T.; Wade, James D.
  • Nature Biotechnology, Vol. 35, Issue 2
  • DOI: 10.1038/nbt.3770

Systems Biology: A Brief Overview
journal, March 2002


On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks
journal, June 2017


Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases
journal, November 2017

  • Merilahti, Johannes A. M.; Ojala, Veera K.; Knittle, Anna M.
  • Molecular Biology of the Cell, Vol. 28, Issue 22
  • DOI: 10.1091/mbc.E17-04-0261

Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments
journal, December 2016

  • Goddard, Erica T.; Hill, Ryan C.; Barrett, Alexander
  • The International Journal of Biochemistry & Cell Biology, Vol. 81
  • DOI: 10.1016/j.biocel.2016.10.014

Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators
journal, August 2012

  • Bodenmiller, Bernd; Zunder, Eli R.; Finck, Rachel
  • Nature Biotechnology, Vol. 30, Issue 9
  • DOI: 10.1038/nbt.2317

Intercellular propagation of extracellular signal-regulated kinase activation revealed by in vivo imaging of mouse skin
journal, February 2015


Matrix Metalloproteinase-3 Releases Active Heparin-binding EGF-like Growth Factor by Cleavage at a Specific Juxtamembrane Site
journal, December 1997

  • Suzuki, Masashi; Raab, Gerhard; Moses, Marsha A.
  • Journal of Biological Chemistry, Vol. 272, Issue 50
  • DOI: 10.1074/jbc.272.50.31730

Organogenesis in a dish: Modeling development and disease using organoid technologies
journal, July 2014


Regulated Cleavage of a Contact-Mediated Axon Repellent
journal, August 2000


Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells
journal, October 2000

  • Schuldiner, M.; Yanuka, O.; Itskovitz-Eldor, J.
  • Proceedings of the National Academy of Sciences, Vol. 97, Issue 21
  • DOI: 10.1073/pnas.97.21.11307

Integrins and cadherins join forces to form adhesive networks
journal, March 2011

  • Weber, G. F.; Bjerke, M. A.; DeSimone, D. W.
  • Journal of Cell Science, Vol. 124, Issue 8
  • DOI: 10.1242/jcs.064618

Systems Biology Analysis of Heterocellular Signaling
journal, August 2016


Autocrine, paracrine and juxtacrine signaling by EGFR ligands
journal, October 2005


Highly Multiplexed Subcellular RNA Sequencing in Situ
journal, February 2014


A draft network of ligand–receptor-mediated multicellular signalling in human
journal, July 2015

  • Ramilowski, Jordan A.; Goldberg, Tatyana; Harshbarger, Jayson
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms8866

Eph/ephrin recognition and the role of Eph/ephrin clusters in signaling initiation
journal, October 2013

  • Nikolov, Dimitar B.; Xu, Kai; Himanen, Juha P.
  • Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 10
  • DOI: 10.1016/j.bbapap.2013.04.020

Cellular and molecular basis of wound healing in diabetes
journal, May 2007

  • Brem, Harold; Tomic-Canic, Marjana
  • Journal of Clinical Investigation, Vol. 117, Issue 5
  • DOI: 10.1172/JCI32169

Epithelial Patterning, Morphogenesis, and Evolution: Drosophila Eggshell as a Model
journal, May 2017


Improved Transplanted Stem Cell Survival in a Polymer Gel Supplemented with Tenascin C Accelerates Healing and Reduces Scarring of Murine Skin Wounds
journal, January 2017

  • Yates, Cecelia C.; Nuschke, Austin; Rodrigues, Melanie
  • Cell Transplantation, Vol. 26, Issue 1
  • DOI: 10.3727/096368916X692249

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance
journal, March 2016


Multiplexed ion beam imaging of human breast tumors
journal, March 2014

  • Angelo, Michael; Bendall, Sean C.; Finck, Rachel
  • Nature Medicine, Vol. 20, Issue 4
  • DOI: 10.1038/nm.3488

Mammary Gland Growth Factors: Roles in Normal Development and in Cancer
journal, June 2010


Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types
journal, February 2014


Sensing extracellular matrix: An update on discoidin domain receptor function
journal, August 2006


Extracellular matrix composition determines the transcriptional response to epidermal growth factor receptor activation
journal, April 2001

  • Yarwood, S. J.; Woodgett, J. R.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 8
  • DOI: 10.1073/pnas.081069098

Design and computational analysis of single-cell RNA-sequencing experiments
journal, April 2016


Matrix metalloproteinases: What do they not do? New substrates and biological roles identified by murine models and proteomics
journal, January 2010

  • Rodríguez, David; Morrison, Charlotte J.; Overall, Christopher M.
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1803, Issue 1
  • DOI: 10.1016/j.bbamcr.2009.09.015

SNaPP: Simplified Nanoproteomics Platform for Reproducible Global Proteomic Analysis of Nanogram Protein Quantities
journal, March 2016

  • Huang, Eric L.; Piehowski, Paul D.; Orton, Daniel J.
  • Endocrinology, Vol. 157, Issue 3
  • DOI: 10.1210/en.2015-1821

Keratinocytes Synthesize Enteropeptidase and Multiple Forms of Trypsinogen during Terminal Differentiation
journal, April 2010

  • Nakanishi, Jotaro; Yamamoto, Mami; Koyama, Junichi
  • Journal of Investigative Dermatology, Vol. 130, Issue 4
  • DOI: 10.1038/jid.2009.364

Predictive Modeling of Signaling Crosstalk during C. elegans Vulval Development
journal, January 2007


Cutaneous Wound Healing
journal, September 1999


Engineering systems for the generation of patterned co-cultures for controlling cell–cell interactions
journal, March 2011

  • Kaji, Hirokazu; Camci-Unal, Gulden; Langer, Robert
  • Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1810, Issue 3
  • DOI: 10.1016/j.bbagen.2010.07.002

Eph/ephrin molecules--a hub for signaling and endocytosis
journal, November 2010

  • Pitulescu, M. E.; Adams, R. H.
  • Genes & Development, Vol. 24, Issue 22
  • DOI: 10.1101/gad.1973910

The Extracellular Matrix: Not Just Pretty Fibrils
journal, November 2009


Secretory Granule Exocytosis
journal, April 2003


Human Organ Culture: Updating the Approach to Bridge the Gap from In Vitro to In Vivo in Inflammation, Cancer, and Stem Cell Biology
journal, September 2017

  • Al-Lamki, Rafia S.; Bradley, John R.; Pober, Jordan S.
  • Frontiers in Medicine, Vol. 4
  • DOI: 10.3389/fmed.2017.00148

Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data
journal, April 2005


Comprehensive proteomic characterization of stem cell-derived extracellular matrices
journal, June 2017


Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context
journal, January 2010

  • Joslin, Elizabeth J.; Shankaran, Harish; Opresko, Lee K.
  • Molecular BioSystems, Vol. 6, Issue 7
  • DOI: 10.1039/c003921g

Lack of CXC Chemokine Receptor 3 Signaling Leads to Hypertrophic and Hypercellular Scarring
journal, April 2010

  • Yates, Cecelia C.; Krishna, Priya; Whaley, Diana
  • The American Journal of Pathology, Vol. 176, Issue 4
  • DOI: 10.2353/ajpath.2010.090564

Growth factors in development, transformation, and tumorigenesis
journal, January 1991


Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor
journal, July 2001

  • Swindle, C. Scott; Tran, Kien T.; Johnson, Terry D.
  • The Journal of Cell Biology, Vol. 154, Issue 2
  • DOI: 10.1083/jcb.200103103

Quantitative analysis of gradient sensing: towards building predictive models of chemotaxis in cancer
journal, April 2012

  • Hughes-Alford, Shannon K.; Lauffenburger, Douglas A.
  • Current Opinion in Cell Biology, Vol. 24, Issue 2
  • DOI: 10.1016/j.ceb.2012.01.001

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE
journal, October 2017


An Orphan Receptor Tyrosine Kinase Family Whose Members Serve as Nonintegrin Collagen Receptors
journal, December 1997


Spatial Range of Autocrine Signaling: Modeling and Computational Analysis
journal, October 2001


Shedding light on sheddases: role in growth and development
journal, January 2002


Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway
journal, July 2016


Network Analysis of Epidermal Growth Factor Signaling Using Integrated Genomic, Proteomic and Phosphorylation Data
journal, March 2012


Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution
journal, April 2003

  • Schenk, Susann; Hintermann, Edith; Bilban, Martin
  • The Journal of Cell Biology, Vol. 161, Issue 1
  • DOI: 10.1083/jcb.200208145

Tenascin cytotactin epidermal growth factor-like repeat binds epidermal growth factor receptor with low affinity
journal, June 2007

  • Iyer, Anand Krishnan V.; Tran, Kien T.; Borysenko, Christopher W.
  • Journal of Cellular Physiology, Vol. 211, Issue 3
  • DOI: 10.1002/jcp.20986

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
journal, June 2016


Self-Organization of Polarized Cell Signaling via Autocrine Circuits: Computational Model Analysis
journal, January 2004


Affinity Regulates Spatial Range of EGF Receptor Autocrine Ligand Binding
journal, October 2002


Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor
journal, May 1999

  • Dong, J.; Opresko, L. K.; Dempsey, P. J.
  • Proceedings of the National Academy of Sciences, Vol. 96, Issue 11
  • DOI: 10.1073/pnas.96.11.6235

PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing: Growth factors and cytokines in wound healing
journal, September 2008


High-throughput fluorescence microscopy for systems biology
journal, July 2006

  • Pepperkok, Rainer; Ellenberg, Jan
  • Nature Reviews Molecular Cell Biology, Vol. 7, Issue 9, p. 690-696
  • DOI: 10.1038/nrm1979

Skin tissue repair: Matrix microenvironmental influences
journal, January 2016


Proteomic Identification of Cellular Protease Substrates Using Isobaric Tags for Relative and Absolute Quantification (iTRAQ)
journal, August 2007

  • Dean, Richard A.; Smith, Derek; Overall, Christopher M.
  • Current Protocols in Protein Science, Vol. 49, Issue 1
  • DOI: 10.1002/0471140864.ps2118s49

Diverse Signaling Pathways Activated by Growth Factor Receptors Induce Broadly Overlapping, Rather Than Independent, Sets of Genes
journal, June 1999


Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry
journal, March 2014

  • Giesen, Charlotte; Wang, Hao A. O.; Schapiro, Denis
  • Nature Methods, Vol. 11, Issue 4
  • DOI: 10.1038/nmeth.2869

Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression
journal, January 2015


The Membrane-anchoring Domain of Epidermal Growth Factor Receptor Ligands Dictates Their Ability to Operate in Juxtacrine Mode
journal, June 2005

  • Dong, Jianying; Opresko, Lee K.; Chrisler, William
  • Molecular Biology of the Cell, Vol. 16, Issue 6
  • DOI: 10.1091/mbc.E04-11-0994