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| Status |
Public on Oct 02, 2023 |
| Title |
Oncogenic GNAS drives a gastric phenotype in Intraductal Papillary Mucinous Neoplasms of the pancreas |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are cyst-like precursor lesions that give rise to 25% of pancreatic ductal adenocarcinomas (PDAC). While ~90% of cases are diagnosed before cancer forms, metrics and markers by which to determine if an IPMN will progress are currently lacking. Overall, 96% of IPMNs harbor KRAS (~80%) and/or GNAS (~66%) driver mutations and IPMN may be classified as either gastric, intestinal, or pancreatobiliary type. Recently, we identified a shared program of pyloric type metaplasia between pancreatic and gastric injury. Here, we combined immunostaining, RNA-sequencing, molecular biology, and analysis of patient samples to identify major drivers of this program in IPMN. Methods Single cell RNA-sequencing datasets of human IPMN were assayed for markers of pyloric-type metaplasia. 37 IPMN patient samples were immunostained using MxIHC for MUC5AC, CD44v9, and AQP5. KrasG12D and GnasR201C expression was modified in IPMN cell lines to identify transcriptomic programs driven by each oncogene, and in combination. Gene sets were compared to murine and human gastric cell types. Transcriptomic drivers were identified and manipulated in vitro. Candidate driver expression was evaluated by immunostaining of patient IPMN and graded. Results Analysis of published bulk and scRNA-seq IPMN datasets revealed expression of previously described markers of pyloric type metaplasia. Marker expression was confirmed in patient samples. Manipulation of KrasG12D and GnasR201C expression in IPMN cell lines identified the relative contributions of each oncogene to this gastric phenotype. Regulon analysis suggests that transcription factors SPDEF, CREB3L1, and CREB3L4 amplify this program in response to GnasR201C expression. All transcription factors were expressed in patient IPMN samples. Conclusions In response to oncogenic mutation(s), IPMN form in the pancreas and express markers of pyloric type metaplasia. KrasG12D and GnasR201C expression drive this program through independent and synergistic mechanisms that result in amplified expression of mucins and gastrokines, consistent with the phenotype identified in vivo.
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| Overall design |
Cell lines with doxycyline-inducible human GNASR201C expression were grown with or without doxycycline and with siRNA targeting Kras, Gnas, both in combination, or control
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| Contributor(s) |
DelGiorno KE, Tan MB, Ivanov S, Jyotsana N |
| Citation missing |
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| Submission date |
Sep 28, 2023 |
| Last update date |
Oct 11, 2023 |
| Contact name |
Kathleen E DelGiorno |
| E-mail(s) |
kathydelgiorno@gmail.com
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| Organization name |
Vanderbilt University
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| Department |
Cell and Developmental Biology
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| Lab |
DelGiorno
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| Street address |
465 21st Ave S
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| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (48)
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| Relations |
| BioProject |
PRJNA1022058 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE244280_10007_normalized_counts.csv.gz |
3.5 Mb |
(ftp)(http) |
CSV |
| GSE244280_10007_raw_counts.csv.gz |
1.1 Mb |
(ftp)(http) |
CSV |
| GSE244280_9522_normalized_counts.csv.gz |
3.0 Mb |
(ftp)(http) |
CSV |
| GSE244280_9522_raw_counts.csv.gz |
903.4 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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