Differential glycosylation of collagen modulates lung cancer stem cell subsets through β1 integrin-mediated interactions.

In lung cancer, CD133+ cells represent the subset of cancer stem cells (CSCs) able to sustain tumor growth and metastatic dissemination. CSCs function is tightly regulated by specialized niches composed of both stromal cells and extracellular matrix proteins (ECM), mainly represented by collagen. The relevance of collagen glycosylation, a fundamental post-translational modification controlling several biological processes, in regulating tumor cell phenotype remains however largely unexplored. To investigate the bioactive effects of differential ECM glycosylation on lung cancer cells, we prepared collagen films functionalized with glucose (Glc-collagen) and galactose (Gal-collagen) exploiting a neoglycosylation approach based on a reductive amination of maltose and lactose with the amino residues of collagen lysines. We demonstrate that culturing of tumor cells on collagen determines a glycosylation-dependent positive selection of CSCs and triggers their expansion/generation. The functional relevance of CD133+ CSCs increase was validated in vivo, proving an augmented tumorigenic and metastatic potential. High expression of integrin β1 in its active form is associated with an increased proficiency of tumor cells to sense signaling from glycosylated matrices (glyco-collagen) and to acquire stemness features. Accordingly, inhibition of integrin β1 in tumor cells prevents CSCs enrichment, suggesting that binding of integrin β1 to Glc-collagen subtends CSCs expansion/generation. We provide evidence suggesting that collagen glycosylation could play an essential role in modulating the creation of a niche favorable for the generation and selection/survival of lung CSCs. Interfering with this cross talk may represent an innovative therapeutic strategy for lung cancer treatment.