Oncogenic GNAS drives a pyloric-type transcriptomic program in pancreatic intraepithelial papillary mucinous neoplasms
Bibliographic record
Abstract
BACKGROUND & AIMS: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions of the pancreas which can serve as precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia (ADM), an injury repair program associated with pancreatic tumorigenesis, is characterized by a pyloric-type transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for SPEM markers and to identify molecular drivers of this program. METHODS: Published RNA-seq studies of IPMN were assessed for SPEM markers, which were validated by immunostaining in patient samples. Murine cell lines expressing Kras G12D +/- GNAS R201C were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify drivers of SPEM in the pancreas. Expression of candidate drivers was evaluated in patient samples by RNA-seq and immunostaining and a role for SPDEF was investigated. RESULTS: SPEM markers were identified in human IPMN. GNAS R201C drove expression of these markers in murine cell lines and siRNA targeting of GNAS R201C or Kras G12D demonstrates that GNAS R201C amplifies a mucinous phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. CONCLUSIONS: De novo expression of a pyloric-type/SPEM phenotype has been identified in pancreatitis, oncogenic Kras G12D -driven pancreatic neoplasia, and in Kras G12D ;GNAS R201C -driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. IPMN-specific GNAS R201C drives a SPEM phenotype characterized by the formation of mucus producing cells at the expense of other lineages. AMR was supported by NIH T32GM139400. AM is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, the Sheikh Khalifa Bin Zayed Al-Nahyan Foundation and NIH (U01CA200468, U54CA274371, U24CA274274, R01CA220236). M.C.B.T is supported by a Vanderbilt Digestive Disease Research Center Pilot and Feasibility Grant (P30 DK058404) and a Nikki Mitchell Foundation Pancreas Club Seed Grant. M.C.B.T and N.J. are supported by The Department of Defense (DOD W81XWH2211121-1). The DelGiorno laboratory is supported by the Vanderbilt Ingram Cancer Center Support Grant (NIH/NCI P30 CA068485), the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer (NIH/NCI 5P50 CA236733), the Vanderbilt Digestive Disease Research Center (NIH/NIDDK P30 DK058404), an American Gastroenterological Association Research Scholar Award (AGA2021-13-02), NIH/NIGMS R35 GM142709, The Department of Defense (DOD W81XWH2211121), The Sky Foundation, Inc (AWD00000079), and Linda’s Hope (Nashville, TN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".