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 in vivo 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 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 α2,6-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 α2,6-linked sialic acids, facilitate niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant breast tumor.

中文翻译：

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2,6-连接的唾液酸的异质性增强了乳腺癌上皮的侵袭。

恶性转化细胞表型的异质性和其表面异常聚糖的表达是迄今为止尚未相互联系的癌症的两个突出标志。在本文中，我们确定了特定聚糖键的不同水平：体内乳腺癌细胞内的α2,6-连接唾液酸和文化。从三阴性乳腺癌细胞系MDA-MB-231中选出两个具有中等水平且相对较高的细胞表面α2,6-连锁唾液酸水平的群体后，两个群体（分别表示为中等和较高的2,6-Sial细胞分别）在早期传代中稳定地保持其水平。通过连续培养，中等的2，6-Sial细胞概括了未分选品系的异质性，而高的2，6-Sial细胞则没有这种趋势。与高2,6-Sial细胞相比，中2,6-Sial对应物显示出对重组细胞外基质（ECM）的粘附性更高，并且以单细胞入侵的速度更快。发现两个亚系中α2，6-连接的唾液酸的水平与特定糖基转移酶ST6GAL1的表达一致。稳定击倒高2,6-Sial细胞中的ST6GAL1增强了其侵袭性。当一起培养时，中等的2,6-Sial细胞差异性地迁移到生长的类瘤样共培养物的边缘，而高浓度的2,6-Sial细胞形成了中央体积。根据我们的实验结果校准的基于Cellts Potts模型的计算环境中的多尺度模拟表明，可能由α2,6-连接的唾液酸调节的不同水平的细胞-ECM粘附力促进了高侵袭性细胞的壁ches作为侵袭性细胞有效地离心迁移。恶性乳腺癌的前部。