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bioRxiv · 10.64898/2026.06.22.733748

Inflammation-driven reprogramming of goblet cells underlies the onset of serrated adenomas in colon cancer

Verhagen, M.·Guerra, E.·Joosten, R.·Sacchetti, A.·Sun, W.·Lila, K.·Nigg, A.·Ahmed, E.·Saadeh, H.·Bosch, T.·Hendrickx, W.·Roelands, J.·Vries, A.·Doukas, M.·Fodde, R.
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Abstract

In the context of inflammation, fully committed and post-mitotic cell lineages can initiate intestinal tumorigenesis in the mouse through dedifferentiation and acquisition of revival stem cell (RSC) features1,2. Likewise, by means of machine-learning analysis of whole-genome mutation spectra, the secretory goblet cell was predicted as the most frequent cell-of-origin (COO) of colon cancer in inflammatory bowel disease (IBD) patients2. Of note, even among sporadic (non-IBD) colon cancer patients, goblet cells were predicted as the most common differentiated COO of cancer in the colonic epithelium2, suggestive of the main role played by diet-induced inflammation in the onset of a large proportion of malignancies of the large bowel. However, how goblet cells respond to inflammation and reprogram their identity to become potential tumor-initiating cells remains unclear. Here, by taking advantage of publicly available single-cell RNAseq data from colonic tissues of ulcerative colitis (UC) patients3, we have characterized the inflammation-driven reprogramming of goblet cells. By means of an RNA velocity-based computational approach, we show that the mucus-producing goblet cells acquire an aberrant proliferative state earmarked by MUC5AC+ expression. Trajectory analysis of serrated adenoma cells4 reveal aberrant goblet cells as an intermediate state in the transition to revival stem cells, notably more common in BRAF-mutant cases. In support of these findings, COO predictions using whole-genome mutation spectra from a cohort of sporadic colon cancers5 connect tumors with a predicted goblet origin to BRAF mutations and reveal transcriptional remnants of the aberrant goblet cell state.

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Verhagen, M., Guerra, E., Joosten, R., Sacchetti, A., Sun, W., Lila, K., Nigg, A., Ahmed, E., Saadeh, H., Bosch, T., Hendrickx, W., Roelands, J., Vries, A., Doukas, M., Fodde, R.. 2026-06-23. Inflammation-driven reprogramming of goblet cells underlies the onset of serrated adenomas in colon cancer. https://doi.org/10.64898/2026.06.22.733748

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