Publications by authors named "Sarah A Woelke"

5 Publications

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Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.

Neoplasia 2016 09;18(9):541-52

Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development.
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http://dx.doi.org/10.1016/j.neo.2016.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031867PMC
September 2016

Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.

Genes Dev 2016 09 15;30(17):1943-55. Epub 2016 Sep 15.

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;

The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
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http://dx.doi.org/10.1101/gad.283499.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066238PMC
September 2016

Brief, pre-learning stress reduces false memory production and enhances true memory selectively in females.

Physiol Behav 2014 Apr 21;128:270-6. Epub 2014 Feb 21.

Department of Pharmaceutical & Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA; College of Pharmacy and Program for Novel Therapeutics in Neurological and Psychiatric Disorders, Roseman University of Health Sciences, Henderson, NV, USA.

Some of the previous research on stress-memory interactions has suggested that stress increases the production of false memories. However, as accumulating work has shown that the effects of stress on learning and memory depend critically on the timing of the stressor, we hypothesized that brief stress administered immediately before learning would reduce, rather than increase, false memory production. In the present study, participants submerged their dominant hand in a bath of ice cold water (stress) or sat quietly (no stress) for 3 min. Then, participants completed a short-term memory task, the Deese-Roediger-McDermott paradigm, in which they were presented with 10 different lists of semantically related words (e.g., candy, sour, sugar) and, after each list, were tested for their memory of presented words (e.g., candy), non-presented unrelated "distractor" words (e.g., hat), and non-presented semantically related "critical lure" words (e.g., sweet). Stress, overall, significantly reduced the number of critical lures recalled (i.e., false memory) by participants. In addition, stress enhanced memory for the presented words (i.e., true memory) in female, but not male, participants. These findings reveal that stress does not unequivocally enhance false memory production and that the timing of the stressor is an important variable that could mediate such effects. Such results could have important implications for understanding the dependability of eyewitness accounts of events that are observed following stress.
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http://dx.doi.org/10.1016/j.physbeh.2014.02.028DOI Listing
April 2014

Brief, pre-retrieval stress differentially influences long-term memory depending on sex and corticosteroid response.

Brain Cogn 2014 Mar 6;85:277-85. Epub 2014 Feb 6.

Department of Pharmaceutical & Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA; College of Pharmacy and Program for Novel Therapeutics in Neurological and Psychiatric Disorders, Roseman University of Health Sciences, Henderson, NV 89014, USA.

Previous work has indicated that stress generally impairs memory retrieval. However, little research has addressed discrepancies that exist in this line of work and the factors that could explain why stress can exert differential effects on retrieval processes. Therefore, we examined the influence of brief, pre-retrieval stress that was administered immediately before testing on long-term memory in males and females. Participants learned a list of 42 words varying in emotional valence and arousal. Following the learning phase, participants were given an immediate free recall test. Twenty-four hours later, participants submerged their non-dominant hand in a bath of ice cold (Stress) or warm (No Stress) water for 3 min. Immediately following this manipulation, participants' memory for the word list was assessed via free recall and recognition tests. We observed no group differences on short-term memory. However, male participants who showed a robust cortisol response to the stress exhibited enhanced long-term recognition memory, while male participants who demonstrated a blunted cortisol response to the stress exhibited impaired long-term recall and recognition memory. These findings suggest that the effects of brief, pre-retrieval stress on long-term memory are sex-specific and mediated by corticosteroid mechanisms.
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http://dx.doi.org/10.1016/j.bandc.2014.01.010DOI Listing
March 2014

Pre-learning stress that is temporally removed from acquisition exerts sex-specific effects on long-term memory.

Neurobiol Learn Mem 2013 Feb 22;100:77-87. Epub 2012 Dec 22.

Department of Psychology, Sociology, & Criminal Justice, Ohio Northern University, Ada, OH 45810, USA.

We have examined the influence of sex and the perceived emotional nature of learned information on pre-learning stress-induced alterations of long-term memory. Participants submerged their dominant hand in ice cold (stress) or warm (no stress) water for 3 min. Thirty minutes later, they studied 30 words, rated the words for their levels of emotional valence and arousal and were then given an immediate free recall test. Twenty-four hours later, participants' memory for the word list was assessed via delayed free recall and recognition assessments. The resulting memory data were analyzed after categorizing the studied words (i.e., distributing them to "positive-arousing", "positive-non-arousing", "negative-arousing", etc. categories) according to participants' valence and arousal ratings of the words. The results revealed that participants exhibiting a robust cortisol response to stress exhibited significantly impaired recognition memory for neutral words. More interestingly, however, males displaying a robust cortisol response to stress demonstrated significantly impaired recall, overall, and a marginally significant impairment of overall recognition memory, while females exhibiting a blunted cortisol response to stress demonstrated a marginally significant impairment of overall recognition memory. These findings support the notion that a brief stressor that is temporally separated from learning can exert deleterious effects on long-term memory. However, they also suggest that such effects depend on the sex of the organism, the emotional salience of the learned information and the degree to which stress increases corticosteroid levels.
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http://dx.doi.org/10.1016/j.nlm.2012.12.012DOI Listing
February 2013