SUMMARY 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 (CR). CR acts by reducing mTOR complex 1 (mTORC1) signaling in Paneth cells, and the ISC-enhancing effects of CR can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced mTORC1 activation in Paneth cells during CR abolishes their effects on ISCs. Finally, increased expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR), mediates the effects of CR 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.

BACKGROUND Tumors metastasizing to the pancreas are rare, and published series are limited by few patients treated for extended periods of time. Renal cell cancer (RCC) is the most common primary tumor metastasizing to the pancreas. Our aim was to describe the clinicopathologic characteristics and patient outcomes in a modern series of patients who underwent metastasectomy, with an emphasis on RCC. STUDY DESIGN Retrospective review of all pancreatic resections between January 1993 and October 2009. RESULTS We identified 40 patients with a median age of 62 years; 55% were female. Patients most commonly presented with abdominal pain (47.5%). Operations performed included 10 pancreaticoduodenectomies, 1 middle, 23 distal, 3 total pancreatectomies, and 3 enucleations. Primary cancers were RCC (n = 20), ovarian (n = 6), sarcoma (n = 3), colon (n = 3), melanoma (n = 2), and others (n = 6). Median survival for all patients after metastasectomy was 4.4 years. Median survival after metastasectomy for RCC was 8.7 years, and the 5-year actuarial survival was 61%. For RCCs, pancreas was the first site of an extrarenal recurrence in 85% and was synchronous with the primary in 5% of patients. There was no survival difference if the time interval to metastasis was shorter than the median (8.7 years), if tumor nodules were multiple or bigger than the median (3 cm), or if the pancreas was not the first site of metastases. CONCLUSIONS An aggressive approach to lesions metastatic to the pancreas is often warranted if the patient can be rendered free of disease. Although patients with RCC can experience long-term survival after metastasectomy, survival is less favorable for other primary tumors.

Perineural invasion is a stronger predictor for recurrence and survival than tumor size, depth of infiltration, lymph node involvement, and type of resection in patients with duodenal adenocarcinoma.