Abstract A070: Comparison of pancreatic cancer mouse models identifies potential drivers of tumor initiation and progression
Notice bibliographique
Résumé
Abstract The five-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is currently 11% [CP1] and by 2030 PDAC is expected to become the second leading cause of cancer related death. Understanding PDAC initiation and maintenance is important for the advancement of treatment. Mouse models allow us to study the mechanisms of PDAC initiation and progression. The most common genetically engineered mouse model (GEMM) of PDAC utilizes a knock-in of Cre recombinase [FB2] into the pancreatic transcription factor 1a (Ptf1a)locus to drive pancreas specific oncogenic KRAS expression. Alternative GEMMs express Cre recombinase from the Mist1/Bhlha15 locus (Mist1-CreER) or from elastase enzyme promoter-driven constructs (Ela-CreER). How these models differ in their ability to promote neoplasia is unknown. We hypothesized that differences in GEMMs may provide insight into mechanisms of PDAC initiation and progression. Here, we compare the tamoxifen-inducible Ptf1a-CreER, [FB3] Mist1-CreER and Ela-CreER models in their response to oncogenic KRAS expression. KRASG12D was induced with tamoxifen gavage 6-8 weeks postpartum and caerulein was used to induce pancreatitis. Histological analyses (H&E and IHC for amylase, cytokeratin 19, Fos and Jun) were performed on fixed tissue to assess associated phenotypic changes. Tissues from Ptf1a-CreER, Mist1-CreER and Ela-CreER mice were harvested 3 weeks after tamoxifen administration and processed for RNA sequencing. Phenotypically, in the presence of oncogenic KRAS and after pancreatitis induction, Ptf1a-CreER pancreata exhibited extensive tissue remodeling - acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) - with a dense fibroinflammatory response in contrast to both Mist1-CreER and Ela-CreER pancreata. Mist1-CreER and Ela-CreER pancreata had much more variable penetrance with tissues often showing little to no ADM and PanINs despite oncogenic KRAS expression and prior pancreatitis. At the gene expression level, Mist1-CreER pancreata showed fewer differentially expressed genes when compared to wild type tissue than Ptf1a-CreER under the same conditions. In total, less than 70 differentially expressed genes were common between the two models. Members of the AP-1 transcriptional complex (fos and c-jun) previously implicated in neoplastic progression were specifically increased only in Ptf1a-CreER mice.[FB4] Taken together, our histological, and transcriptional data indicates mice lacking one copy of Ptf1a (Ptf1a-CreER) undergo more dramatic histological changes after pancreatitis injury and oncogenic KRAS induction when compared to the GEMMs with both copies of Ptf1a intact. Additionally, mice in the Ptf1a-CreER group show a more marked molecular response to oncogenic KRAS induction, suggesting the absence of a single copy of the acinar fate transcription factor Ptf1a disrupted pancreatic homeostasis and poised it for transformation. Further comparison of PDAC GEMMs will yield clearer insight into mechanisms of PDAC initiation and progression. Citation Format: Joyce K. Thompson, Fatemeh Mousavi, Justine Lau, Emily Wu, Christopher Pin, Filip Bednar. Comparison of pancreatic cancer mouse models identifies potential drivers of tumor initiation and progression [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 A070.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,003 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».