Abstract (Background) Pancreatic ductal adenocarcinoma (PDAC) had been thought to arise from pancreatic ductal cells. However, recent studies using genetically engineered mouse model revealed that both pancreatic acinar and ductal cells can serve as cells of origin with distinct biological properties. However, it has not been determined whether these lineage-associated features are preserved in human PDAC or influence clinical outcomes. (Methods) We performed RNA-sequencing of PDAC tissue from 40 patients, who underwent surgical resection without neoadjuvant chemotherapy. Patients were classified into two groups, acinar- or ductal-subtype, based on cell-of-origin signatures derived from data set of mouse models. This classification strategy was also applied to human PDAC cell lines, followed by in vitro drug sensitivity assays. (Results) Eighteen tumors (45%) were classified as acinar-subtype and 22 (55%) as ductal-subtype. The ductal-subtype had significantly shorter overall survival than the acinar-subtype (median 26.5 vs. 54.0 months; p 0.01). In addition, the multivariate analysis revealed the ductal cell-derived tumor signature as the sole factor for poor prognosis (HR=3.97, 95%CI: 1.33-11.9, p=0.01). Among 33 patients who experienced recurrence, 23 received gemcitabine-based chemotherapy. Long-term disease control (10 months) was observed more frequently in the acinar-subtype than in the ductal-subtype (63.6% vs 16.7%, p=0.02). In vitro, MIAPaCa-2, classified as an acinar-subtype cell line, exhibited greater sensitivity to gemcitabine (p 0.01) and paclitaxel (p 0.05) compared with the ductal-subtype cell lines, specifically AsPC-1 and Capan-2, consistent with the clinical findings. (Conclusion) Our study highlighted the clinical significance of the cell-of-origin-based classification in PDAC. The ductal-subtype PDAC requires intensive follow-up as a high-risk group of postoperative recurrence, and the acinar-subtype PDAC can have a long-term disease maintenance with gemcitabine-based regimens. Citation Format: Tatsuya Kikuchi, Soichiro Ako, Hideaki Kinugasa, Tomoyuki Honda, Fumio Otsuka, Motoyuki Otsuka. Clinical significance of a cell-of-origin-based classification in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3888.
Kikuchi et al. (Fri,) studied this question.