Dedifferentiation-mediated stem cell niche maintenance in early-stage ductal carcinoma in situ progression: insights from a multiscale modeling study.

ABSTRACT

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is sensitive to perturbations in several key mechanisms that are instrumental to early disease development. Our studies reveal that long-term maintenance of multipotent stem-like cell niches within the tumor are dependent on cell dedifferentiation plasticity, and that disease progression will become arrested due to dilution of the multipotent stem-like population in the absence of dedifferentiation. We have identified dedifferentiation rates necessary to maintain biologically relevant multipotent cell populations, and also explored quantitative relationships between dedifferentiation rates and disease progression rates, which may potentially help to optimize the efficacy of emerging anti-cancer stem cell therapeutics.