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

TitleThe cancer glycocalyx mechanically primes integrin-mediated growth and survival.
Publication TypeJournal Article
Year of Publication2014
AuthorsPaszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK, Godula K, Hudak JE, Lakins JN, Wijekoon AC, Cassereau L, Rubashkin MG, Magbanua MJ, Thorn KS, Davidson MW, Rugo HS, Park JW, Hammer DA, Giannone G, Bertozzi CR, Weaver VM
JournalNature
Volume511
Issue7509
Pagination319-25
Date Published2014 Jul 17
ISSN1476-4687
KeywordsAnimals, Breast, Cell Line, Tumor, Cell Proliferation, Cell Survival, Fibroblasts, Glycocalyx, Glycoproteins, Humans, Immobilized Proteins, Integrins, Mice, Molecular Targeted Therapy, Mucin-1, Neoplasm Metastasis, Neoplasms, Neoplastic Cells, Circulating, Protein Binding, Receptors, Cell Surface
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.

DOI10.1038/nature13535
Alternate JournalNature
PubMed ID25030168
Grant List1U01 ES019458-01 / ES / NIEHS NIH HHS / United States
2R01GM059907-13 / GM / NIGMS NIH HHS / United States
AI082292-03A1 / AI / NIAID NIH HHS / United States
CA138818-01A1 / CA / NCI NIH HHS / United States
GM59907 / GM / NIGMS NIH HHS / United States
K99 EB013446-02 / EB / NIBIB NIH HHS / United States
U54CA143836-01 / CA / NCI NIH HHS / United States
U54CA163155-01 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
Weaver