MicroRNA expression abnormalities in pancreatic endocrine and acinar tumours are associated with distinctive pathologic features and clinical behavior
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73350 | GEO | 2015/10/30
SECONDARY ACCESSION(S): PRJNA296801
REPOSITORIES: GEO
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Project description:We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumours and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumour types. A neoplastic cellularity higher than 90% was obtained by cryostat enrichment. RNA was extracted with Trizol (Invitrogen, Carlsbad, CA) from 10 20-μm thick cryostat sections, checking the cell composition of the sample every five sections. RNA integrity was confirmed using the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). microRNA microarray (Ohio State University Comprehensive Cancer Center, version 2.0) contains probes for 460 mature microRNAs spotted in quadruplicate (235 homo sapiens, 222 mus musculus, and three Arabidopsis thaliana) with annotated active sites. Often, more than one probe set exists for a given mature microRNA.
2015-10-30 | E-GEOD-73350 | biostudies-arrayexpress
Project description:Serine protease inhibitor Kazal type 3 (Spink3) is a trypsin inhibitor in the pancreas. Spink3-/- pancreatic acinar cells are dead with excessive autophagy at birth (p0.5). To prove the role of nonapoptotic cell death with autophagy, we generated by transgenic technology the pancreas of Spink3-/-;XKI/+ mice contained both normal and dying acinar cells with autophagy. In this new mouse model, chronic inflammation occurred in the pancreas, indicating that some signals from nonapoptotic dead cell induce chronic inflammation in the pancreas. All samples were the pancreas at p0.5. Sample 1 and 2 are the pancreas from wild type (Spink3+/+, control) mice. Sample 3 and 4 are the pancreas from Spink3-/-, which all pancreatic acinar cells show induced nonapoptotic cell death with autophagy. Sample 5 and 6 are the pancreas from Spink3-/-XKI/+, about half acinar cells are normal, but other acinar cells show induced nonapoptotic cell death with autophagy.
2016-07-16 | E-GEOD-48946 | biostudies-arrayexpress
Project description:Serine protease inhibitor Kazal type 3 (Spink3) is a trypsin inhibitor in the pancreas. Spink3-/- pancreatic acinar cells are dead with excessive autophagy at birth (p0.5). To prove the role of nonapoptotic cell death with autophagy, we generated by transgenic technology the pancreas of Spink3-/-;XKI/+ mice contained both normal and dying acinar cells with autophagy. In this new mouse model, chronic inflammation occurred in the pancreas, indicating that some signals from nonapoptotic dead cell induce chronic inflammation in the pancreas.
2016-07-16 | GSE48946 | GEO
Project description:Pancreas volume or mass varies more than 3-fold among adult humans. The heterogeneity is likely the result of genetics, diseases, and nutrition. Dietary protein intake and blood amino acid levels are known to affect pancreas mass, but the underlying mechanism is not well understood. The goal of this study is to determine how increased blood amino acid level (hyperaminoacidemia) induces pancreas expansion.Multiple complementary mouse and zebrafish models were used to study the impact of hyperaminoacidemia on pancreatic mass, acinar cell size and proliferation. Blood amino acid levels were manipulated by dietary protein content, or by pharmacologic or genetic interruption of glucagon signaling (IGS). The activation of mammalian target of rapamycin complex 1 (mTORC1) and Yes-associated protein 1 (YAP) were determined by pS6 and YAP staining. Sirolimus administration in mice and knockdown of solute carrier family 38 member 5b (slc38a5b) and yap/taz in zebrafish were used to determine the role of mTORC1, SLC38A5 and YAP/TAZ in acinar cell proliferation and pancreas expansion. We found that the IGS-induced pancreas expansion was the result of acinar cell proliferation and hypertrophy. Hyperaminoacidemia was the likely mediator as pancreas expansion was blunted by a low protein diet in mice and by knocking down the most highly expressed amino acid transporter gene, slc38a5b, in zebrafish lacking both glucagon receptor genes (gcgr-/-). In GCGR-Ab treated mice, inhibition of mTORC1 attenuated both hyperplasia and hypertrophy of acinar cells. There was a gene expression signature of YAP activation in acinar cells, consistent with increased YAP-expressing acinar cells in GCGR-Ab treated mice and increased fraction of acinar cells with nuclear YAP1 in gcgr-/- zebrafish. Knocking down yap1 or taz decreased mTORC1 activity and acinar cell hyperplasia and hypertrophy in gcgr-/- zebrafish. Hyperaminoacidemia leads to acinar cell proliferation and hypertrophy via activation of both mTORC1 and YAP pathways. The study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
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Project description:Despite reduced function and volume of the exocrine pancreas in type 1 diabetes, literature describing the histology and the molecular biological profile in this area is limited. Here, the density of acinar cells was examined adjacent to and at varying distances from islets and the transcriptome was analyzed on laser capture microdissected (LCM) tissue from organ donors with and without type 1 diabetes. We demonstrate preserved acinar nuclei density in type 1 diabetes and find no support of acinar atrophy in pancreata devoid of insulin. The density of acinar nuclei was unaltered in type 1 diabetes. Principal component analysis of the transcriptomes of acinar tissue extracted from various areas of the pancreas showed no apparent clustering based on disease status, and few differentially expressed genes were discovered. However, when performing GSEA, transcriptional alterations were present in the acinar tissue independently of the distance from islets. Two gene sets were enriched in all exocrine regions; Myc Targets V2 and Estrogen Response Early. The alteration of these is a possible link to the increased incidence of pancreatic cancer in type 1 diabetes. Taken together, these new data shed light on the pathogenesis of type 1 diabetes and its involvement of the entire pancreas.
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Project description:Acinar cells make up the majority of all cells in the pancreas, yet the source of new acinar cells during homeostasis remains unknown. Using multicolor lineage-tracing and organoid-formation assays, we identified the presence of a progenitor-like acinar cell subpopulation. These cells have long-term self-renewal capacity, albeit in a unipotent fashion. We further demonstrate that binuclear acinar cells are terminally differentiated acinar cells. Transcriptome analysis of single acinar cells revealed the existence of a minor population of cells expressing progenitor markers. Interestingly, a gain of the identified markers accompanied by a transient gain of proliferation was observed following chemically induced pancreatitis. Altogether, our study identifies a functionally and molecularly distinct acinar subpopulation and thus transforms our understanding of the acinar cell compartment as a pool of equipotent secretory cells.
2016-10-31 | GSE80032 | GEO
Project description:Our team has previously characterized a subpopulation of ductal progenitor cells with progenitor-like characteristics. These cells proliferate in response to stimulation of the BMP pathway by BMP-7 and, following withdrawal of this growth factor, differentiate into all three adult epithelial pancreatic lineages (ductal, acinar and endocrine), both in vitro and after transplantation. scRNAseq analysis of sorted human pancreatic ductal cells has confirmed the existence of progenitor-like clusters whose transcriptomic signature suggests a role for stress-mediated de-differentiation in the acquisition of their stemness. Importantly, the application of cell trajectory analyses upon integration of this ductal dataset with other published datasets that also include endocrine and acinar cells revealed the potential existence of ducto-acinar and ducto-endocrine differentiation axes. However, these conclusions were qualified by the fact that they came from the amalgamation of multiple datasets from many different donors, processed and analyzed in different ways, and also in the absence of a defined regenerative stimulus whose effect could be investigated in a truly continuous manner. We hypothesized that the sequential scRNAseq of same-donor HPSs would address the above constraints and allow us, for the first time, to dissect cell fate changes at the single cell level in response to BMP-7 in a “whole human pancreas” setting. To test this hypothesis, we conducted the longitudinal scRNAseq analysis of human pancreatic slices (HPSs) subjected to a 10-day regimen consisting of 5 days of exposure to BMP-7 followed by 5 days without. The most immediately apparent observation is the transcriptomic heterogeneity of the ductal and acinar compartments, which most earlier analyses (based on isolated islet samples that at best contained a small proportion of ductal and acinar cell types) have failed to detect. With the exception of a recent single nucleus RNAseq report, no other similar study thus far has presented the field with a true whole-pancreas analysis where the different cell types of the organ retain their natural proportion. Integration of single-cell datasets obtained from same-donor HPSs at different time points, or in the presence or absence of treatment, allowed us to conduct cell trajectory analyses using true temporal information, rather than by pseudotemporal inferences. This integration revealed population shifts consistent with BMP-7-mediated progenitor cell activation, the blurring of ductal/acinar boundaries, the formation of clear ducto-acinar-endocrine differentiation axes and, notably, the appearance of transitional insulin-producing cell populations. These findings contrast with the pattern observed in untreated controls, whose cluster composition and distribution remain largely unchanged with time –another observation that further confirms the robustness of the HPS model to faithfully mirror the cellular makeup of the human pancreas over a 10-day period. In summary, our study provides the first longitudinal scRNAseq analysis of whole human pancreatic tissue, mapping true cell fate trajectories in a manner that was simply not possible prior to the development of long-term HPS culture techniques. These experiments unequivocally confirm pancreatic plasticity in a dynamic fashion and validate the reliability of this novel human-based model for countless other research applications.
2023-10-30 | GSE223713 | GEO
Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.
2018-07-03 | GSE114576 | GEO
Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.
2018-07-03 | GSE114567 | GEO
Project description:Acinar and ductal cells are the major epithelial cell types in the exocrine pancreas, but which of these serves as the cell-of-origin in human PDAC has been debated. Our mouse models have demonstrated that oncogenic Kras expression and Trp53 loss in pancreatic acinar or ductal cells can lead to pancreatic cancer. Here, we performed gene expression profiling of bulk acinar cell-derived and ductal cell-derived mouse pancreatic tumors to identify the transcriptomic profiles.
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