The cancer glycocalyx mechanically primes integrin-mediated growth and survival

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. Metastatic cancer cells are shown to have a tendency towards forming a bulky glycocalyx owing to the production of large glycoproteins, and this cancer-associated glycocalyx has a mechanical effect on the spatial organization of integrins — by funnelling integrins into adhesions, integrin clustering and signalling is promoted, which leads to enhanced cell survival and proliferation. The composition of the cellular glycocalyx — a glycoprotein/polysaccharide layer that coats the cell surface — changes with the changing nature of a cell through processes such as tissue differentiation and disease. Valerie Weaver and colleagues set out to establish whether changes in glycocalyx composition in cancer cells contribute to the cancer phenotype. They find that bulky glycocalyx is a feature of metastatic cancer cells, resulting from the production of large glycoproteins. The bulky glycocalyx physically traps glycoprotein adhesion molecules called integrins, which in turn promote a signalling regime that favours cell survival and proliferation. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with aggressive breast cancers. These findings suggest that the glycocalyx and its molecular constituents are attractive targets for therapeutic interventions aimed at normalizing transmembrane receptor signalling.