Glycobiological Regulation of Breast Cancer Invasion
Pally, Dharma Tejeshwar Reddy
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Invasiveness of cancer is the predominant reason behind mortality associated with the disease. Although long under active investigation, fundamental aspects of the early steps of cancer invasion and metastasis are still poorly understood. One such aspect, the aberrant expression of glycans and their binding proteins (lectins), is among the earliest-demonstrated and pervasive hallmarks of malignant transformation, the consequences of which remain elusive. In this thesis, two glycopathological questions relating to breast cancer progression are investigated. In the first problem, evidence is presented for heterogeneity of a specific glycan linkage: α2,6-linked sialic acids within breast cancer epithelia. Upon sorting out two populations with moderate- and relatively higher- cell surface expression of α2,6-linked sialic acids, from the triple negative breast cancer cell line MDA-MB-231, both populations (denoted as medium- and high- 2,6-Sial cells respectively) are shown to stably retain their levels in early passages. The medium 2,6-Sial cells shows greater plasticity (recapitulating eventually the heterogeneity of the unsorted population), and higher adhesion to, and invasion through, ECM, than the high 2,6-Sial cells. The expression of 2,6-Sial and the associated phenotypes is shown to be dependent on the expression of a specific glycosyltransferase, ST6GAL1. The differential adhesion between the two populations is proposed to have consequences for the ‘unjamming’ transition and localization of medium 2,6-Sial cells to the edge of growing tumoroid-like cultures. Notwithstanding the dynamics of cell-surface α2,6-linked sialic acids, an intriguing localization of α2,3-linked sialic acids is observed in the ECM proximal to breast cancer cells. In the second problem, the role of Galectin-9 (GAL-9) in breast cancer invasion is investigated. A member of the tandem-repeat (having two distinct carbohydrate recognition domains (bi-CRD)) class of galectins, mRNA levels of GAL-9 are shown to be elevated in invasive breast cancer cell lines and the protein is elevated in tumor epithelia from sections of patients with breast cancer. Perturbing GAL-9 levels is shown to correlate with the adhesion and invasion of cancer epithelia to, and through, ECM, respectively. Intriguingly, the consequences of GAL-9 on invasion is observed to be dependent on its cleavage to monoCRD galectins with the N-CRD fragment (but not C-CRD fragment) able to phenocopy the effects of the full-length counterpart. Taken together, the above observations add an unexplored (glycobiological) dimension to the interactions between cancer cells and their surrounding ECM, enriching our understanding of how the tumor microenvironment contributes to cancer progression.