Modeling the Impact of Dedifferentiation on Colorectal Cancer Growth and Chemo-Immunotherapy Response.

Tumor cell heterogeneity poses a significant challenge in the treatment of colorectal cancer, with dedifferentiation being a key factor in the emergence and maintenance of such heterogeneity. Does dedifferentiation necessarily promote colorectal cancer growth? What are its regulatory mechanisms in treatment response? These critical questions remain insufficiently understood. To investigate this issue, we develop a cancer cell population dynamics model. Our findings reveal that dedifferentiation impacts cancer growth in complex and varied patterns. Specifically, dedifferentiation can either facilitate or hinder cancer growth, with the outcomes depending on the dedifferentiation probability and the growth rates of different types of tumor cells. Subsequently, we consider the implications of dedifferentiation for various treatment strategies. Chemotherapy, which simultaneously promotes cell death and induces dedifferentiation, shows variable efficacy, potentially leading to tumor shrinkage or growth. In contrast, the combination of chemotherapy and high-intensity immunotherapy significantly enhances therapeutic outcomes, achieving more stable tumor control. These findings underscore the importance of incorporating dedifferentiation dynamics into colorectal cancer growth models and treatment designs, highlighting the advantages of combination therapy in overcoming the limitations of monotherapy.