The cancer glycocalyx mechanically primes integrin-mediated growth and survival

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast / cytology
  • Breast / metabolism
  • Breast / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Fibroblasts
  • Glycocalyx / chemistry
  • Glycocalyx / metabolism*
  • Glycoproteins / metabolism*
  • Humans
  • Immobilized Proteins / chemistry
  • Immobilized Proteins / metabolism
  • Integrins / chemistry
  • Integrins / metabolism*
  • Mice
  • Molecular Targeted Therapy
  • Mucin-1 / metabolism
  • Neoplasm Metastasis / pathology
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Neoplastic Cells, Circulating
  • Protein Binding
  • Receptors, Cell Surface

Substances

  • Glycoproteins
  • Immobilized Proteins
  • Integrins
  • Mucin-1
  • Receptors, Cell Surface