Deficient cell-cell cohesion is linked with lobular localization in simplified models of lobular carcinoma in situ...

Lobular carcinoma in situ (LCIS) is a precursor of invasive lobular carcinoma of the breast. LCIS cells lack cell-cell cohesion due to the loss of E-cadherin. LCIS cells grow in mammary lobules rather than in ducts. The etiology of this pattern, especially its dependence on cellular cohesion, is incompletely understood. We simulated passive intra-glandular scattering of carcinoma in situ (CIS) cells in an ultra-simplified hollow mold tissue replica (HMTR) and a discrete-time mathematical model featuring particles of variable sizes representing single cells (LCIS-like particles) or groups of cohesive carcinoma cells (DCIS-like particles). The HMTR features structures reminiscent of a mammary duct with associated lobules. The discrete mathematical model characterizes spatial redistribution over time and includes transition probabilities between ductal or lobular localizations. Redistribution of particles converged toward an equilibrium depending on particle size. Strikingly, equilibrium proportions depended on particle properties, which we also confirm in a continuous-time mathematical model that considers controlling lobular properties such as crowding. Particles of increasing size, representing CIS cells with proficient cohesion, showed increasingly higher equilibrium ductal proportions. Our investigations represent two conceptual abstractions implying a link between loss of cell-cell cohesion and lobular localization of LCIS, which provide a much-needed logical foundation for studying the connections between collective cell behavior and cancer development in breast tissues. In light of the findings from our simplified modeling approach, we discuss multiple avenues for near-future research that can address and evaluate the redistribution hypothesis mathematically and empirically.