Title | The cancer glycocalyx mechanically primes integrin-mediated growth and survival. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Paszek 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 |
Journal | Nature |
Volume | 511 |
Issue | 7509 |
Pagination | 319-25 |
Date Published | 2014 Jul 17 |
ISSN | 1476-4687 |
Keywords | Animals, 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. |
DOI | 10.1038/nature13535 |
Alternate Journal | Nature |
PubMed ID | 25030168 |
Grant List | 1U01 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 |