Abstract C017: Exogenous carcinogenic exposures in early-onset pancreatic carcinogenesis: Insights from alcohol and tobacco-driven models
Notice bibliographique
Résumé
Abstract Introduction: The increasing incidence of early-onset pancreatic ductal adenocarcinoma (PDAC), defined as diagnosis before age 50, coincides with rising global exposures to carcinogens such as alcohol and tobacco during critical developmental windows. Emerging evidence suggests these exposures reprogram epithelial and stromal compartments early in life, priming the pancreas for oncogenic transformation. However, the molecular events linking these exposures to early tumorigenesis remain underexplored. Methods: To investigate alcohol- and tobacco-driven mechanisms of early-onset pancreatic carcinogenesis, we utilized both syngeneic orthotopic models and genetically engineered mouse models (GEMMs), including Ptf1aCreERTM/+, Ptf1aCreERTM/+;LSL-KrasG12D/+ (KC), KPC (KC with mutant p53) and Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) lines (both tumor-bearing and non-tumor). Chronic cigarette smoke exposure and alcoholic chronic pancreatitis (ACP) were initiated in early adulthood. single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, immunophenotyping, and histopathology were performed to delineate epithelial, stromal, and immune cell changes. Acinar lineage tracing using Rosa26tdTomato/+ was integrated to track acinar-to-ductal metaplasia (ADM). Human PDAC (smokers and non-smokers) and chronic pancreatitis tissues were used for cross-species validation. Results: Both alcohol and tobacco exposure accelerated neoplastic progression and induced pronounced fibroinflammatory transformation of the tumor microenvironment (TME). scRNA-seq revealed the early emergence of ductal-like epithelial clusters with elevated Sox9, Pdx1, and Hnf1b-hallmarks of ADM. Ethanol- and smoke-exposed mice showed impaired acinar regeneration, persistent epithelial reprogramming, and an augmented PanIN burden. Immune profiling showed expanded MDSCs, M2 macrophages, and regulatory T cells in exposed models, mirroring immune-suppressive signatures seen in early-onset human PDAC samples. We show the molecular mechanism involved and the differences in cellular signaling between tobacco-induced and alcohol-induced carcinogenesis. Lineage tracing confirmed that acinar cells serve as a source for ductal lesions under repeated inflammatory insults, especially in the presence of oncogenic Kras. Conclusions: Early exposure to carcinogens from external sources, like tobacco and alcohol, triggers molecular changes in pancreatic epithelium and immune stroma, which accelerate neoplastic transformation. Such exposures result in persistent fibroinflammatory damage, encourage ADM, and establish a pro-tumorigenic microenvironment. Our research provides a mechanistic understanding of the increase in early-onset PDAC and advocates for using integrated technologies-GEMMs, scRNA-seq, and lineage tracing-to model early-life exposures as crucial for intervention targets. These findings emphasize the importance of prevention strategies aimed at modifiable exogenous risk factors during the critical stages of PDAC development. Citation Format: Nagaraj Nagathihalli. Exogenous carcinogenic exposures in early-onset pancreatic carcinogenesis: Insights from alcohol and tobacco-driven models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C017.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».