Publication Date:
2014-07-18
Description:
Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paszek, Matthew J -- DuFort, Christopher C -- Rossier, Olivier -- Bainer, Russell -- Mouw, Janna K -- Godula, Kamil -- Hudak, Jason E -- Lakins, Jonathon N -- Wijekoon, Amanda C -- Cassereau, Luke -- Rubashkin, Matthew G -- Magbanua, Mark J -- Thorn, Kurt S -- Davidson, Michael W -- Rugo, Hope S -- Park, John W -- Hammer, Daniel A -- Giannone, Gregory -- Bertozzi, Carolyn R -- Weaver, Valerie M -- 1U01 ES019458-01/ES/NIEHS NIH HHS/ -- 2R01GM059907-13/GM/NIGMS NIH HHS/ -- AI082292-03A1/AI/NIAID NIH HHS/ -- CA138818-01A1/CA/NCI NIH HHS/ -- GM59907/GM/NIGMS NIH HHS/ -- K99 EB013446-02/EB/NIBIB NIH HHS/ -- R00 EB013446/EB/NIBIB NIH HHS/ -- R01 CA138818/CA/NCI NIH HHS/ -- R01 GM059907/GM/NIGMS NIH HHS/ -- T32 GM066698/GM/NIGMS NIH HHS/ -- U01 CA151925/CA/NCI NIH HHS/ -- U54 CA143836/CA/NCI NIH HHS/ -- U54 CA163155/CA/NCI NIH HHS/ -- U54CA143836-01/CA/NCI NIH HHS/ -- U54CA163155-01/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 17;511(7509):319-25. doi: 10.1038/nature13535. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA [3] School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, USA [4] Laboratory for Atomic and Solid State Physics and Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York 14853, USA. ; 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA. ; 1] Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France [2] CNRS, Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France. ; Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA. ; 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [3] Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, USA. ; Department of Chemistry, University of California, Berkeley, California 94720, USA. ; 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [2] Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA. ; Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA. ; National High Magnetic Field Laboratory and Department of Biological Science, The Florida State University, Tallahassee, Florida 32310, USA. ; Departments of Chemical and Biomolecular Engineering and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2] Department of Molecular Biology, University of California, Berkeley, California 94720, USA [3] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA. ; 1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA [3] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [4] Departments of Anatomy and Bioengineering and Therapeutic Sciences and Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030168" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Breast/cytology/metabolism/pathology
;
Cell Line, Tumor
;
Cell Proliferation
;
Cell Survival
;
Fibroblasts
;
Glycocalyx/chemistry/*metabolism
;
Glycoproteins/*metabolism
;
Humans
;
Immobilized Proteins/chemistry/metabolism
;
Integrins/chemistry/*metabolism
;
Mice
;
Molecular Targeted Therapy
;
Mucin-1/metabolism
;
Neoplasm Metastasis/pathology
;
Neoplasms/*metabolism/*pathology
;
Neoplastic Cells, Circulating
;
Protein Binding
;
Receptors, Cell Surface
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
