Abstract A028: Metastatic potential defines an orthogonal axis of transcriptomic heterogeneity that predicts chemotherapy response and tumor microenvironment architecture in pancreatic ductal adenocarcinoma
Raymond E. Preston, Hongyu Huang, Margaret A. Hall, Richard Moffitt, Udhayvir S. Grewal, Olatunji B. Alese, Gregory B. Lesinski, Jesse S. HandlerAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) has traditionally been classified into two overarching transcriptomic subtypes—classical and basal—which have been associated with distinct clinical behaviors and therapeutic responses. We recently identified a previously unrecognized transcriptomic axis governing metastatic colonization, quantified by MetScore, representing a second major dimension of PDAC cell-state heterogeneity. However, how metastatic cell state intersects with classical–basal subtype to influence therapeutic response and tumor microenvironment (TME) architecture has remained unknown.
Methods:
To address this question, we partnered with the Pancreatic Cancer Action Network to analyze the Know Your Tumor cohort (n=504), the largest clinically annotated transcriptomic dataset in PDAC to date. This real-world cohort enabled integrated analyses of tumor transcriptomic state, chemotherapy outcomes, and TME composition with unprecedented statistical power.
Results:
Stratification of tumors along both the classical–basal and metastatic cell-state axes identified molecular subgroups with distinct therapeutic vulnerabilities. Among patients with classical MetScore-high PDAC, 5-fluorouracil (5FU)-based chemotherapy yielded a significantly higher objective response rate than gemcitabine-based therapy (35.9% vs. 15.6%; OR 3.05, 95% CI 1.17–7.91; Fisher's exact p=0.029), whereas no differential benefit was observed in the remaining three molecular subgroups. These findings demonstrate that integrating both transcriptomic axes more accurately predicts chemotherapy response than either classification alone, identifying a molecular subgroup with selective sensitivity to 5FU-based therapy. This framework has immediate translational relevance for precision chemotherapy selection and will inform chemotherapy backbone choice in KRAS inhibitor trials, as well as treatment following progression on KRAS inhibitor monotherapy. We further investigated the relationship between transcriptomic state and the TME. While both basal subtype and high MetScore converged on enrichment of tumor-associated macrophages, they exhibited opposing associations with cancer-associated fibroblasts (CAFs): CAF abundance increased with basal subtype probability but decreased with increasing MetScore. These findings demonstrate that the two transcriptomic axes differentially shape stromal remodeling despite shared inflammatory features, revealing previously unappreciated complexity in PDAC TME organization.
Conclusions:
Together, these data establish metastatic cell state as an independent and clinically actionable dimension of PDAC biology that complements classical–basal subtype classification. Integrating MetScore with existing transcriptomic subtyping improves prediction of chemotherapy response while providing new insights into TME organization. These findings position MetScore as a predictive biomarker for precision therapeutic stratification and provide a molecular framework to guide treatment selection in the evolving era of KRAS-targeted therapy.
Citation Format:
Raymond E. Preston, Hongyu Huang, Margaret A. Hall, Richard Moffitt, Udhayvir S. Grewal, Olatunji B. Alese, Gregory B. Lesinski, Jesse S. Handler. Metastatic potential defines an orthogonal axis of transcriptomic heterogeneity that predicts chemotherapy response and tumor microenvironment architecture in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A028.