Abstract C075: The loss of ATRX induces a sex-specific progression of pancreatic ductal adenocarcinoma in the presence of oncogenic KRASG12D
Bibliographic record
Abstract
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related deaths primarily due to a lack of effective early screening and the tumor microenvironment increasing resistance to chemotherapy. Somatic mutation in oncogenic KRASG12D appears in 97% of PDAC patients, however, the addition of environmental and epigenetic stressors are required to promote PDAC initiation and progression from acinar cells. We are elucidating the mechanism by which a loss of α-thalassemia, mental-retardation, X-linked (ATRX), a SWI/SNF chromatin remodeling protein, potentiates acinar cells to develop neoplastic lesions in females. Young et al. have confirmed that female mice with a loss of Atrx, combined with KRASG12D, have shown increased acinar-to-duct cell metaplasia (ADM), increased fibrosis, inflammation, and pancreatic intraepithelial neoplasias (PanINs) lesions relative to mice expressing KRASG12D and Atrx. I hypothesize that a loss of ATRX function increases sensitivity to KRASG12D in PDAC by affecting DNA damage and repair pathways and altering gene expression in acinar cells in a sex-specific fashion. Methods: Mice with an acinar-specific Atrx deletion and oncogenic KRASG12D expression were generated by mating to mice targeting an inducible creERT to the Ptf11α gene (PtflacreERT). Mice were gavaged with tamoxifen and pancreatic injury was induced in these mice (Ptf11αcreERT KRASLSLG12DAtrxfl/fl) with cerulein 10 days later. Mice are monitored for two and five weeks following cerulein treatment and pancreatic tissue was collected for molecular, biochemical, and histological analysis. In addition, pre-neoplastic pancreatic organoid cultures +/- ATRX expression were generated to assess differences in growth rates and chemotherapy resistance. Results: Preliminary results have shown increased sensitivity to chronic pancreatitis is predicted to be observed specifically in KRASG12D Atrx-/- female pancreatic tissue and derived organoids. Conversely, a protective effect stimulated by a loss of ATRX is observed in KRASG12D Atrx-/- male mice, indicated by less ADM/PanIN lesions and greater acinar cells. Discussion: A healthier prognosis in Atrx-/-, KRAS activated male mice suggests that the interaction between ATRX and various scaffold proteins (PRC2, DAXX, EZH2, etc.) alters chromosomal architecture, possibly altering gene expression via X chromosome inactivation or reactivation. Sex-specific differences in pancreatic tissue phenotype of Atrx-/- mice are predicted to arise from differential effects of ATRX in triggering acinar cell genomic instability in female mice to prevent the resolution of dsDNA breaks via non-homologous end joining to sensitize acinar cells to oncogenic KRAS. Future experiments will focus on establishing pre-neoplastic organoid lines derived from inflamed murine pancreata to elucidate the signalling pathway of ATRX that likely stimulates a differential gene and protein expression involved in a better prognosis in KRASG12D activated, Atrx-/- male mice. Citation Format: Aswin Sureshkumar, Phyo Win, Christopher Pin. The loss of ATRX induces a sex-specific progression of pancreatic ductal adenocarcinoma in the presence of oncogenic KRASG12D [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C075.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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".