Biology subjects

Kopp, J. L.

Publications and source records attributed to Kopp, J. L..

7 recordsLinked to original sources

bioRxiv2026

Female biases in islet cell gene expression, alpha cell number, and glucagon are present early in postnatal life

Biological sex significantly affects glucose homeostasis. Sex differences in insulin sensitivity in peripheral tissues play a role in this difference; however, a growing body of evidence suggests sex differences in islet cells also contribute to differential glucose homeostasis. Studies in rodent and human models have identified sex differences in alpha- and beta-cell gene expression, in islet cell composition, metabolism, and stress responses, and in circulating levels of glucoregulatory hormones. However, most of these studies used adult humans or mice, leaving the age at which these differences emerge less clear. We performed a detailed characterization of glucose homeostasis and islet biology in young male and female mice from two mouse strains widely used in diabetes research to model both Type 1 (non-obese diabetic, NOD) and Type 2 diabetes (C57BL/6J). We uncovered male-female differences in islet cell gene expression and composition, and in circulating levels of glucagon. Importantly, these differences were reproducible across both models and were present prior to diabetes-like phenotypes. Together, our data suggest sex differences in aspects of islet biology begin early in postnatal life.

physiology↗

bioRxiv2026

Endogenous insulin mediates dynamic coordination between pancreatic cancer and systemic metabolism

Pancreatic ductal adenocarcinoma (PDAC) is commonly associated with obesity, diabetes, and cachexia. The pancreatic anabolic hormone, insulin, is implicated in each of these metabolic diseases, but how insulin levels affect tumor growth and relevant host physiological factors, was unclear. To address this, we transplanted orthotopic PDAC patient-derived organoids into mice consuming a hyperinsulinemia-inducing high-fat diet (HFD). We found that insulin concentrations were higher in tumors compared to circulation. Genetically reducing insulin levels reduced PDAC growth, particularly in HFD-fed mature male mice. In turn, we found the presence of pancreatic tumors increased glucose clearance and limited the expected dietary-induced gains in insulin, weight and fat mass. Interestingly, tumor growth in normal-chow-fed mice, but not HFD-fed mice, was associated with declining circulating insulin levels, as well as declines in fat and muscle mass. Together, these data provide new insights into the complex, insulin-centred interplay between PDAC and the hosts systemic metabolism that underlie cancer-associated metabolic dysfunction.

cancer biology↗

bioRxiv2023

Acvr1b loss promotes formation of precancerous lesions from acinar and ductal cells of origin

Background & AimsPancreatic ductal adenocarcinoma (PDAC) can develop from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas, however, the cell type predominantly affected by these genetic changes remains unclear. MethodsWe investigated the contribution of cellular origin by inducing IPMN associated mutations-KRASG12D expression and Acvr1b loss - specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/flmice) or ductal (Sox9CreER;KrasLSL- G12D;Acvr1bfl/flmice) cells in mice. We then performed MRI imaging and a thorough histopathological analysis of their pancreatic tissues. ResultsThe loss of Acvr1b increased the development of PanIN and IPMN-like lesions when either acinar and ductal cells expressed a Kras mutation. MRI, immunohistochemistry and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and PanIN when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b. ConclusionThese findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.

cancer biology↗

bioRxiv2021

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics

Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that a [~]50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice could be achieved with reduced insulin production. However, only female mice remained normoglycemic and only the gene dosage of rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Here, we studied PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent specific Ins1 gene, and possessing one or two alleles of the wild-type Ins2 gene to modulate insulin production. High-fat diet induced hyperinsulinemia was transiently and modestly reduced, without affecting glucose tolerance, in male and female mice with only one allele of Ins2. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell populations, which were highly represented in our analysis. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. These data suggest a role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

cancer biology↗

bioRxiv2019

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/floxmice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.

cancer biology↗

bioRxiv2019

Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function in vivo

Pancreas is a vital organ composed of exocrine and endocrine cells that aid digestion of food and regulate blood glucose levels. Perturbations in the function of pancreatic cells leads to the development of life-burdening and/or threatening diseases such as diabetes and pancreatic cancer. Thus, it is critical to understand the molecular check-points that maintain normal pancreas physiology. MicroRNAs (miRNAs) are small non-coding RNAs involved in regulating gene expression in normal and diseased tissues. Several miRNAs have tissue-specific patterns consistent with crucial functions in many biological processes. Yet, there is limited knowledge about the role of pancreas-specific miRNAs in pancreatic pathologies. Here, we report that miR-216a is a conserved, pancreas-specific miRNA that is expressed in both endocrine and exocrine cells. Deletion of miR-216a in mice leads to reduced {beta}-cell mass and a reduction in islet size under both chow and high-fat diet feeding conditions. We show that inhibition of miR-216a increases apoptosis and decreases cell proliferation in {beta}- and exocrine cells. Smad7 is upregulated in miR-216a deficient islets and cell cycle and proliferation are among the most significantly regulated biological processes in miR-216 knockout pancreata. Re-introduction of miR-216a in the pancreatic cancer line, PANC-1, increases cell migration more than 2-fold. In vivo, deletion of miR-216a in the pancreatic cancer prone mouse line KrasG12D;Ptf1aCreER inhibits the propensity of pancreatic cancer precursor lesions. Our study identifies miR-216a as an important pancreas-specific miRNA which may have implications for both diabetes and pancreatic cancer.

physiology↗

bioRxiv2019

Endogenous insulin contributes to pancreatic cancer development

Obesity and early-stage type 2 diabetes (T2D) increase the risk for many cancers, including pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking obesity and T2D to cancer have not been established, preventing targeted interventions. Arguments have been made that hyperinsulinemia, hyperglycemia, or inflammation could drive cancer initiation and/or progression1. Hyperinsulinemia is a cardinal feature of obesity and T2D, and is independently associated with PDAC incidence and mortality2-4, even in non-obese people5. Despite ample human epidemiological evidence linking hyperinsulinemia to PDAC, there is no direct in vivo evidence of a causal role for endogenous insulin in cancer in any system. Using mice with reduced insulin gene dosage6, 7, we show here that a modest reduction in endogenous insulin production leads to a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in high fat diet-fed mice expressing the KrasG12D oncogene8. The significant reduction in PanIN lesions occurred in the absence of changes in fasting glucose. Reduced insulin also led to a ~50% reduction in pancreatic fibrosis, suggesting that endogenous insulin drives PanIN development, in part, via its pro-fibrotic effects on the stroma surrounding acinar cells and PanIN. Collectively, our data indicate that endogenous insulin hypersecretion contributes causally to pancreatic cancer development. This suggests a modest reduction in fasting insulin via lifestyle interventions or therapeutics may be useful in cancer prevention.

cancer biology↗