Study reveals critical role of phenotypic switching in cancer tumor formation and spread

A recent study has examined the role of phenotypic switching in cancer cells and its significant impact on the development of isolated tumor foci, which contributes to multifocal tumor formation. The research, conducted by Dr. Zuzanna Szymańska, Dr. Mirosław Andrzej Lachowicz, and their team, was published by Science Direct.

According to this study, a new mathematical model was introduced to investigate how alterations in cancer cell phenotype influence the rate of invasion and metastasis. Through computational simulations that mirror in vivo multifocal breast carcinomas, the research underscored the crucial role of tumor cell plasticity in disease progression and local invasion. Specifically, Szymańska's team found that elevated levels of TGF-β, produced by nearby cancer-associated fibroblast (CAF) cells, instigated a transformation of epithelial cells into mesenchymal cells. This prompted them to migrate away from the primary tumor. "As these mesenchymal cells moved further from the primary tumor and encountered lower TGF-β concentrations," they say, "they reverted to an endothelial cell phenotype, ceasing migration and becoming highly proliferative once again."

While focusing on the formation of isolated tumor foci within a single tissue, the study also suggests that this same mechanism could potentially explain metastases development in distant body parts. It emphasizes the importance of reverse phenotype transition—known as MET—for metastatic colonization. Cancer cells must partially revert to a more epithelial phenotype for metastasis to occur. The researchers say that this insight challenges the conventional view of EMT (epithelial-mesenchymal transition) as being solely responsible for cancer cell dissemination.

The study states that scientists now face the task of deciphering the complex regulatory system governing changes in cancer cell phenotype that promote invasion and metastasis. According to Lachowicz's team, while TGF-β appears to be a key player in this process, it is likely not the only contributor. This suggests a need for a more comprehensive understanding of the regulatory network involved.

The researchers argue that the implications of their study extend to clinical applications, particularly in the context of multifocal breast cancer (MBC). Patients with MBC typically have a poorer prognosis than those with unifocal breast cancer. This disparity has often been attributed to an underestimation of tumor size in MBC cases. The study claims that as the research model continues to evolve, it improves the accuracy of tumor size estimation and assesses the extent of invasive spread. These advancements could reportedly lead to better prognostic outcomes for patients with MBC.

The team also suggests that combining this mathematical model with magnetic resonance imaging (MRI) could be particularly valuable. Given MRI's increasing relevance in breast cancer diagnosis, this combination could enhance disease management and treatment.

Elsevier: Zuzanna Szymańska, et al., Mathematical modelling of cancer invasion: Phenotypic transitioning provides insight into multifocal foci formation, Journal of Computational Science (2024). https://doi.org/10.1016/j.jocs.2023.102175