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Heterogeneity in 2,6-Linked Sialic Acids Potentiates Invasion of Breast Cancer Epithelia.

ABSTRACT: Heterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify differential levels of a specific glycan linkage: ?2,6-linked sialic acids within breast cancer cells in vivo and in culture. Upon sorting out two populations with moderate, and relatively higher, cell surface ?2,6-linked sialic acid levels from the triple-negative breast cancer cell line MDA-MB-231, both populations (denoted as medium and high 2,6-Sial cells, respectively) stably retained their levels in early passages. Upon continuous culturing, medium 2,6-Sial cells recapitulated the heterogeneity of the unsorted line whereas high 2,6-Sial cells showed no such tendency. Compared with high 2,6-Sial cells, the medium 2,6-Sial counterparts showed greater adhesion to reconstituted extracellular matrices (ECMs) and invaded faster as single cells. The level of ?2,6-linked sialic acids in the two sublines was found to be consistent with the expression of a specific glycosyl transferase, ST6GAL1. Stably knocking down ST6GAL1 in the high 2,6-Sial cells enhanced their invasiveness. When cultured together, medium 2,6-Sial cells differentially migrated to the edge of growing tumoroid-like cocultures, whereas high 2,6-Sial cells formed the central bulk. Multiscale simulations in a Cellular Potts model-based computational environment calibrated to our experimental findings suggest that differential levels of cell-ECM adhesion, likely regulated by ?2,6-linked sialic acids, facilitate niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant breast tumor.

SUBMITTER: Pally D

PROVIDER: S-EPMC7844859 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Heterogeneity in 2,6-Linked Sialic Acids Potentiates Invasion of Breast Cancer Epithelia.

Pally Dharma D Pramanik Durjay D Hussain Shahid S Verma Shreya S Srinivas Anagha A Kumar Rekha V RV Everest-Dass Arun A Bhat Ramray R

ACS central science 20210104 1

Heterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify differential levels of a specific glycan linkage: α2,6-linked sialic acids within breast cancer cells <i>in vivo</i> and in culture. Upon sorting out two populations with moderate, and relatively higher, cell surface α2,6-linked sialic acid levels from the triple-negative br ...[more]

PMID: 33532574

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Project description:Mammosphere and breast tumoursphere culture have gained popularity as in vitro assays for propagating and analysing normal and cancer stem cells. Whether the spheres derived from different sources or parent cultures themselves are indeed single entities enriched in stem/progenitor cells compared to other culture formats has not been fully determined. We surveyed sphere-forming capacity across 26 breast cell lines, immunophenotyped spheres from six luminal- and basal-like lines by immunohistochemistry and flow cytometry and compared clonogenicity between sphere, adherent and matrigel culture formats using in vitro functional assays. Analyses revealed morphological and molecular intra- and inter-sphere heterogeneity, consistent with adherent parental cell line phenotypes. Flow cytometry showed sphere culture does not universally enrich for markers previously associated with stem cell phenotypes, although we found some cell-line specific changes between sphere and adherent formats. Sphere-forming efficiency was significantly lower than adherent or matrigel clonogenicity and constant over serial passage. Surprisingly, self-renewal capacity of sphere-derived cells was similar/lower than other culture formats. We observed significant correlation between long-term-proliferating-cell symmetric division rates in sphere and adherent cultures, suggesting functional overlap between the compartments sustaining them. Experiments with normal primary human mammary epithelia, including sorted luminal (MUC1(+)) and basal/myoepithelial (CD10(+)) cells revealed distinct luminal-like, basal-like and mesenchymal entities amongst primary mammospheres. Morphological and colony-forming-cell assay data suggested mammosphere culture may enrich for a luminal progenitor phenotype, or induce reversion/relaxation of the basal/mesenchymal in vitro selection occurring with adherent culture. Overall, cell line tumourspheres and primary mammospheres are not homogenous entities enriched for stem cells, suggesting a more cautious approach to interpreting data from these assays and careful consideration of its limitations. Sphere culture may represent an alternative 3-dimensional culture system which rather than universally 'enriching' for stem cells, has utility as one of a suite of functional assays that provide a read-out of progenitor activity.

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Heterogeneity in 2,6-Linked Sialic Acids Potentiates Invasion of Breast Cancer Epithelia.

Publications

Heterogeneity in 2,6-Linked Sialic Acids Potentiates Invasion of Breast Cancer Epithelia.

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