Abstract C017: Exogenous carcinogenic exposures in early-onset pancreatic carcinogenesis: Insights from alcohol and tobacco-driven models
Bibliographic record
Abstract
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.
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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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".