Phenotypic plasticity, i.e. the capacity of a single cell with a given genotype to acquire multiple phenotypes as a function of its environment, represents one of the most clinically relevant hallmark of cancer as it plays rate-limiting roles along the invasion-metastasis cascade. Somewhat surprisingly, we recently discovered that phenotypic plasticity also plays a crucial role in tumor onset (initiation) and in determining the identity of the cell-of-origin of cancer.

In cancer biology, the dogma predicts that virtually all cancers are initiated in stem cells. By using mouse models and patient-derived colon cancers, we have recently shown that a significant proportion of colon cancers are in fact initiated in post-mitotic and fully differentiated cell lineages. In the context of inflammation, while resident stem cells are suppressed, differentiated cells de-differentiate and acquire specific stem-like features thus contributing to tissue regeneration. However, this mechanism will also increase the relative number of cell targets of tumor initiation. Of note, the prognosis of tumors arisen from differentiated lineages appears to feature decreased overall survival and a distinctive inflammatory profile when compared with those derived from stem cells.

These results can be explained by the recent observation according to which Western lifestyles and in particular Western-style dietary habits can cause a low-grade but chronic and metabolic inflammation (called metaflammation), which might prime committed cell lineages to initiate colon tumorigenesis. At-risk individuals might also include cases of early-onset colon cancer, the incidence of which has risen dramatically in the past few decades.

Essential literature:

1. Verhagen, M. P. et al. Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation. Nat. Genet. 56, 1456–1467 (2024).

2. Verhagen, M.P., Schmitt, M. & Fodde, R. Western lifestyle, metaflammation and the cell of origin of colon cancer. Nat Rev Gastroenterol Hepatol 21, 603–604 (2024). https://doi.org/10.1038/s41575-024-00964-7

3. Christ, A., Lauterbach, M. & Latz, E. Western diet and the immune system: an inflammatory connection. Immunity 51, 794–811 (2019).

4. Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175.e14 (2018).