The cancer cell glycocalyx mechanically primes integrin-dependent growth and survival

Nature (2014)

Paszek M.J., Dufort C.C., Rossier O., Bainer R., Mouw J.K., Godula K., Hudak J.E., Lakins J.N., Wijekoon A., Cassereau L., Rubashkin M.G., Magbanua M.J., Thorn K.S., Davidson M.W., Rugo H.S., Park J.W., Hammer D.A, Giannone G., Bertozzi C.R, Weaver V.M.

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.