Abstract A054: Activating transcription factor 3 promotes KRAS-mediated pancreatic ductal adenocarcinoma
Notice bibliographique
Résumé
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) has ~10% survival 5 years after diagnosis often due to lack of chemotherapeutic response. Unlike many other tumors, pancreatic tumors have a high stromal content and cancer associated fibroblasts (CAFs) play a role in response. To improve patient outcome, we need to determine how tumor and non-tumor cell interactions contribute to PDAC progression. Our laboratory recently showed global deletion of Atf3 in mice expressing oncogenic KRAS (Atf3-/-Ptf1acreERT/+KRASG12D; referred to as APK) reduced preneoplastic lesion progression. However, APK mice also showed increased fibrosis and altered immune cell infiltration and single cell RNA-seq revealed ATF3 expression in tumor and non-tumor cells. These findings suggest ATF3 may affect multiple cell types in PDAC. The goal of this study was to determine the epithelial-specific role ATF3 plays in PDAC initiation. We hypothesize that ATF3 promotes PDAC initiation and progression through epithelial and non-epithelial cell mechanisms. Methods: Mice allowing cre recombinase-inducible KRASG12D activation with (Ptf1acreERT/+KRASG12D) or without Atf3 (APK mice) or combined with Atf3 deletion specific to pancreatic acinar cells (AacinarPK mice) were generated. 2-4 month-old mice from all genotypes were gavaged with tamoxifen to induce cre-mediated recombination. Ten and twelve days following cre activation, pancreatic injury was induced by cerulein. Two weeks post injury, general morphology, tissue histology, and gene expression was compared. In some cases, cells were isolated from pancreatic tissue and prepared for 3-dimensional organoid cultures. Results: Histological analysis indicated AacinarPK mice had fewer high-grade PanIN lesions compared to both APK or Ptf1acreERT/+KRASG12D mice with reduced lesion size, based on the PanIN marker CK19, and pERK accumulation, a downstream mediator of KRAS. In addition, Ptf1acreERT/+KRASG12D, APK, and AacinarPK show differences in stromal makeup. While analysis of the stromal compartment shows no change in overall CAF accumulation, IHC for a-SMA showed reduced accumulation of myCAFs in APK tissue. There is also a reduction in immune cell infiltration when ATF3 is deleted, based on CD45 staining. Analysis of organoid cultures showed loss of ATF3 reduced compact morphology of organoid structures and reduced mesenchymal cell transformation. Conclusion and Future Directions: This analysis supports an epithelial-specific role for ATF3 in KRASG12 -mediated PDAC. Since APK and AacinarPK mice do not show the same phenotype, our data also suggests ATF3 has additional roles in nonepithelial cells. Therefore, cell-specific targeting needs to be considered in treating PDAC. Future experiments will examine ATF3-regulated pathways in the various cell populations found in PDAC. Citation Format: Mickenzie B. Martin, Ye Shen, Christopher Pin. Activating transcription factor 3 promotes KRAS-mediated pancreatic ductal adenocarcinoma [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 A054.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 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 ».