TNF-a alters Dedifferentiation of Enterochromaffin Cells, Redirecting Towards 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 non-endocrine 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 previous <i>in vivo</i> induction of non-neuroendocrine adenomas. However, the addition of TNF-α to the enteroid media induced EC cell clusters in multiple crypts and well differentiated neuroendocrine tumor vs. carcinoma in the absence and presence of gain of Myc function, respectively. These findings suggest that TNF-α blocked EC cell dedifferentiation to ISCs, 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.