Integrated tumour-immune cell response modelling of Luminal A breast cancer details malignant signalling and ST3Gal1 inhibitor induced reversal

Aberrant O-glycosylation of mucin-type glycopeptide 1 (MUC1) is implicated in cancerous cellular processes involving the manipulation of immune response to favour tumour growth and metastasis. There is an unmet need for systems glycobiology models to probe the relationship between MUC1 O-glycosylation and immune cells within the tumour microenvironment. We expand on the sparsely understood MUC1 and immune cell interactions by building a complete systems model that combines the glycosylation network in the tumour cell with downstream biological networks. An ordinary differential equations- based model of the effect of aberrant glycosylation on immune modulation in breast cancer was constructed. The model comprises three interdependent component models that are MUC1-type O-glycosylation in the tumour cell, chemokine secretion in macrophages, and signal transduction in the tumour cells. A comparative CytoCopasi algorithm was developed to sequentially perturb the networks by an aberrant O-glycosylation. Comparative simulations revealed that upregulation of tumour-associated MUC1 sialyl-T antigen in Luminal A breast cancer stimulated the upregulation of the chemokine CXCL5 in tumour-associated macrophages. Consequently, increased CXCL5 binding by the tumour cell led to a positive feedback loop through overactive signal transduction and autocrine CXCL5 production. Finally, perturbing the glycosylation network with the sialyltransferase inhibitor Soyasaponin-I abrogated the cancerous upregulations in the downstream networks.