Person:

Yilmaz, Omer

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.

INTRODUCTION: The prototypic pancreatic ductal adenocarcinoma shows small-caliber glands that are placed within an exuberant desmoplastic stromal reaction. A number of histologic patterns have been described, and the majority of these patterns are genetically and biologically related to conventional ductal adenocarcinomas. In this report we describe our experience with a heretofore undescribed histologic pattern of pancreatic adenocarcinoma that mimics intraductal papillary mucinous carcinoma, both morphologically and radiologically. METHODS: We identified 10 cases of pancreatic adenocarcinoma with large-caliber malignant glands and an intraluminal papillary pattern. The demographic, clinical, radiologic, and outcome data were recorded. In addition to a review of the histologic features we also performed elastin stains, immunohistochemistry for selected oncogenes and tumor suppressor genes including SMAD4. Immunohistochemical staining for MUC proteins was also performed. RESULTS: The median age of the patients was 67 years, and there were 6 women and 4 men. Grossly, the cut surface in 6 of these cases showed an admixture of solid and cystic areas. The papillary cystic architecture was intimately mixed with areas of conventional adenocarcinoma, the latter characterized by invasive small-caliber tubular structures. None of the tumors showed a pure papillary cystic pattern; however, in 8 cases, this was the predominant pattern (>50% of the tumor). The cysts and papillae were lined predominantly by tall columnar hypermucinous epithelium. Elastin fibers were not identified around these dilated malignant cysts and glands. The intratumoral stroma was paucicellular and hyalinized. Seven of the 10 tumors were negative for SMAD4. The lack of pericystic elastin fibers and loss of SMAD4 in the majority of cases argue against these lesions representing an intraductal papillary mucinous neoplasm. All 10 tumors stained for MUC1; focal MUC2 reactivity was noted in 1 case. The majority of cases were positive for MUC5AC (9/10) and MUC6 (8/10). Seven patients died of their disease, whereas 1 patient is alive with widely metastatic disease. Two patients were lost to follow up. CONCLUSIONS: The adenocarcinoma described herein is a unique morphologic pattern of pancreatic ductal adenocarcinoma. The biology and genetics (as estimated by immunohistochemistry) are no different from that of conventional ductal adenocarcinoma but are distinctly different from that