Background & Aims Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. Methods We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1 + or Hoxb6 + fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. Results Although in the healthy pancreas Gli1 + fibroblasts and Hoxb6 + fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1 + fibroblasts expand dramatically, whereas Hoxb6 + cells do not. Conclusions Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1 + and Hoxb6 + fibroblasts and found only Gli1 + expanded to contribute to the stroma during pancreatic carcinogenesis.
Based on two years of observations and engaging in informal
A new pattern of global migration is that of skilled or educated people moving from developed to developing countries in search of work. In this qualitative research study, 41 non-Chinese university instructors teaching in Beijing were asked about their decisions to migrate to the mainland. Foreign professors moved to China for various reasons: it had been their last resort, for research purposes and career advancement, or for adventure. The instructors collectively maintained that teaching at Chinese universities did not have the same level of prestige or respect as teaching at universities in western countries. To combat perceived lower social status, international professors in China rationalized their new temporary positions by creating a positive sense of self and situation. This article describes the ways in which prestige is maintained by professors dealing with perceived social downgrade.
Undocumented workers create social cohesion, which serves as a source of solidarity and identification for individuals who are otherwise pushed to the periphery by the dominant society. This article is based on a larger study examining the personal, social, and working lives of undocumented restaurant workers using an ethnographic approach in conjunction with the life history method. Based on observation of their day-to-day interactions in the restaurant and in conversations, this article discusses the ‘family’ or fictive kin relationship they establish with their co-workers and their employer. Despite their illegal status and low earnings, this group of undocumented workers is able to maintain their dignity, find ways of bringing joy to their lives, and attain a sense of belonging. Integration into the restaurant’s pseudo-family averts feelings of frustration and loneliness that are often the consequences of marginalization.
Background & AimsTissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2α. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2α expression in the pancreas have remained undefined.MethodsWe developed several transgenic mouse models based on the expression of an oxygen-stable form of HIF2α, or indirect stabilization of HIF proteins though deletion of von Hippel-Lindau, thus preventing HIF degradation. Furthermore, we crossed both sets of animals into mice expressing oncogenic KrasG12D in the pancreas.ResultsWe show that HIF2α is not expressed in the normal human pancreas, however, it is up-regulated in human chronic pancreatitis. Deletion of von Hippel-Lindau or stabilization of HIF2α in mouse pancreata led to the development of chronic pancreatitis. Importantly, pancreatic HIF1α stabilization did not disrupt the pancreatic parenchyma, indicating that the chronic pancreatitis phenotype is specific to HIF2α. In the presence of oncogenic Kras, HIF2α stabilization drove the formation of cysts resembling mucinous cystic neoplasm (MCN) in humans. Mechanistically, we show that the pancreatitis phenotype is linked to expression of multiple inflammatory cytokines and activation of the unfolded protein response. Conversely, MCN formation is linked to activation of Wnt signaling, a feature of human MCN.ConclusionsWe show that pancreatic HIF2α stabilization disrupts pancreatic homeostasis, leading to chronic pancreatitis, and, in the context of oncogenic Kras, MCN formation. These findings provide new mouse models of both chronic pancreatitis and MCN, as well as illustrate the importance of hypoxia signaling in the pancreas.
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