TNF-α alters dedifferentiation of enterochromaffin cells, redirecting toward neuroendocrine tumors.

Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting, well-differentiated neuroendocrine tumors of enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Prior studies using TPH1 Cre-ERT2-driven RPM mice [EC cell-targeted RB1 (R) and Trp53 (P) loss and Myc (M) gain] showed nonendocrine adenocarcinomas in the small intestine through dedifferentiation of EC cells to intestinal stem cells, which are prone to transformation. However, these studies were limited by early death from tumors at other sites, leaving the potential for SI-NET development unclear over longer periods. To circumvent this time-limited off-target effect, the present study used intestinal enteroids from RPM mice to examine the effect of RB1 and Trp53 loss with or without gain of Myc function on EC cell-derived tumors. Initial results confirmed the previous in vivo induction of nonendocrine adenoma/adenocarcinoma. However, the addition of TNF-α to the enteroid media induced EC cell clusters in multiple crypts and well-differentiated neuroendocrine tumor versus carcinoma in the absence and presence of gain of Myc function, respectively. These findings suggest that TNF-α blocked EC cell dedifferentiation to intestinal stem cells, promoting their survival and expansion and shifting their fate from intestinal adenoma/carcinoma to a differentiated neuroendocrine tumor type. The present study thus highlights the crucial role of the microenvironment in influencing EC cell-derived tumorigenesis and provides insights into SI-NET development.NEW & NOTEWORTHY Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine. However, the tumorigenesis of these specified tumor types remains poorly understood. The present organoid studies show that the addition of TNF-α to the microenvironment maintains the specificity of EC cells during their transformation to neuroendocrine tumors while blocking their dedifferentiation to ISC-derived adenomas.