The cancer glycocalyx mechanically primes integrin-mediated growth and survival

Matthew J. Paszek, Christopher C. DuFort, Olivier Rossier, Russell Bainer, Janna K. Mouw, Kamil Godula, Jason E. Hudak, Jonathon N. Lakins, Amanda C. Wijekoon, Luke Cassereau, Matthew G. Rubashkin, Mark J. Magbanua, Kurt S. Thorn, Michael W. Davidson, Hope S. Rugo, John W. Park, Daniel A. Hammer, Grégory Giannone, Carolyn R. Bertozzi and Valerie M. Weaver ()
Additional contact information
Matthew J. Paszek: University of California
Christopher C. DuFort: University of California
Olivier Rossier: Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France
Russell Bainer: University of California
Janna K. Mouw: University of California
Kamil Godula: University of California
Jason E. Hudak: University of California
Jonathon N. Lakins: University of California
Amanda C. Wijekoon: University of California
Luke Cassereau: University of California
Matthew G. Rubashkin: University of California
Mark J. Magbanua: Helen Diller Family Comprehensive Cancer Center, University of California
Kurt S. Thorn: University of California
Michael W. Davidson: The Florida State University
Hope S. Rugo: Helen Diller Family Comprehensive Cancer Center, University of California
John W. Park: Helen Diller Family Comprehensive Cancer Center, University of California
Daniel A. Hammer: University of Pennsylvania
Grégory Giannone: Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, F-33000 Bordeaux, France
Carolyn R. Bertozzi: University of California
Valerie M. Weaver: University of California

Nature, 2014, vol. 511, issue 7509, 319-325

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13535

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