The cancer glycocalyx mechanically primes integrin-mediated growth and survival.
Nature. 2014-06-25; 511(7509): 319-325
DOI: 10.1038/nature13535
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1. 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.
Paszek MJ(1), DuFort CC(2), Rossier O(3), Bainer R(2), Mouw JK(4), Godula K(5),
Hudak JE(6), Lakins JN(4), Wijekoon AC(2), Cassereau L(2), Rubashkin MG(2),
Magbanua MJ(7), Thorn KS(8), Davidson MW(9), Rugo HS(7), Park JW(7), Hammer
DA(10), Giannone G(3), Bertozzi CR(11), Weaver VM(12).
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.
Comment in
Nature. 2014 Jul 17;511(7509):298-9.
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.
DOI: 10.1038/nature13535
PMCID: PMC4487551
PMID: 25030168 [Indexed for MEDLINE]