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Nature. 2014 Jul 17;511(7509):319-25. doi: 10.1038/nature13535. Epub 2014 Jun 25.

The cancer glycocalyx mechanically primes integrin-mediated growth and survival.

Author information

1
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.
2
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
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.
4
Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA.
5
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.
6
Department of Chemistry, University of California, Berkeley, California 94720, USA.
7
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.
8
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
9
National High Magnetic Field Laboratory and Department of Biological Science, The Florida State University, Tallahassee, Florida 32310, USA.
10
Departments of Chemical and Biomolecular Engineering and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
11
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.
12
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.

Abstract

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.

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PMID:
25030168
PMCID:
PMC4487551
DOI:
10.1038/nature13535
[Indexed for MEDLINE]
Free PMC Article

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