Clinical Significance of a Cell-Of-Origin-Based Classification in Pancreatic Ductal Adenocarcinoma.

Authors

Tatsuya Kikuchi, Soichiro Ako, Hironari Kato, Hideaki Kinugasa, Masaki Uchida, Takashi Oda, Ryosuke Hirai, Akihiro Matsumi, Kazuya Miyamoto, Hiroyuki Terasawa, Yuki Fujii, Daisuke Uchida, Kazuyuki Matsumoto, Koichiro Tsutsumi, Shigeru Horiguchi, Kazuya Yasui, Tomokazu Fuji, Kosei Takagi, Hirokazu Kato, Tomoyuki Honda, Fumio Otsuka, Motoyuki Otsuka

Published in

Cancer science. Sep 13, 2026. Epub Sep 13, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic options and poor clinical outcomes. Although PDAC has traditionally been thought to arise from ductal epithelial cells, recent studies using genetically engineered mouse models have demonstrated that acinar cells can also serve as a cell of origin, giving rise to tumors with distinct biological properties. Here, we investigated whether such lineage-specific differences are preserved in human PDAC. RNA sequencing was performed on resected specimens from 40 treatment-naïve patients with PDAC, and tumors were classified into Acinar- and Ductal-subtypes using lineage-specific gene expression signatures derived from mouse models. This classification strategy was further applied to human PDAC cell lines, followed by in vitro drug sensitivity assays. Patients with Acinar-subtype tumors had significantly longer overall survival than those with Ductal-subtype tumors (median, 54.0 vs. 26.5 months; p < 0.01), and multivariate analysis identified the ductal cell-derived tumor signature as an independent predictor of poor prognosis (HR, 3.74 [95% CI, 1.41-9.97]; p = 0.01). Among patients who developed postoperative recurrence, Acinar-subtype tumors were associated with more durable disease control (≥ 10 months) following gemcitabine-based chemotherapy than Ductal-subtype tumors (63.6% vs. 16.7%; p = 0.02). Consistently, pancreatic cancer cell lines classified as Acinar-subtype showed greater sensitivity to gemcitabine (p < 0.01) and paclitaxel (p < 0.05). These findings extend the clinical relevance of cell-of-origin signatures beyond prognostic stratification, highlighting the potential of cell-of-origin-based classification for treatment stratification and precision medicine in PDAC.

PMID:
42732876
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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