According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.

按照传统观点，结肠癌起源于干细胞。然而，炎症是结肠癌的一个关键危险因素，已被证明可以抑制肠道干细胞。在这里，我们使用潘氏细胞作为模型来评估分化谱系在小鼠炎症背景下触发肿瘤发生的能力。发生炎症时，潘氏细胞特异性Apc突变会导致肠道肿瘤，这不仅让人想起炎症性肠病患者中出现的肿瘤，还让人想起大部分人类散发性结肠癌。后者可能是由于西式饮食习惯的炎症后果，这是结肠癌的主要危险因素。旨在从患者来源的肿瘤样本中预测癌症细胞起源的机器学习方法证实，在很大一部分散发病例中，结肠癌的起源在于分泌谱系而不是干细胞。