Abstract Notch is a contact-dependent signaling pathway that plays critical roles in spatiotemporal patterning during embryogenesis. Beyond its role in development, Notch signaling regulates tissue patterning in adult organs in response to tissue injury or cancer. In the context of cancer, the role of Notch signaling has been extensively characterized in cancer cells, T cells, and endothelial cells. Our previous work has implicated Notch signaling in the myeloid and fibroblast compartments of the pancreatic tumor microenvironment (TME) in the tumor immune response, an area that has been previously understudied. In our current work we use genetically engineered mouse models to inhibit canonical Notch activation in fibroblasts (Pdgfra CreERT2/+, LSL-DNMAML) and myeloid cells (LysM Cre/+, LSL-DNMAML) separately. In both an orthotopic transplant and genetic model (Ptf1a FlpO/+;FSF-Kras G12D/+) of pancreatic cancer progression, inhibition of fibroblast-specific Notch activation had limited effects on disease progression and the transcriptional profile of the fibroblasts themselves. This is consistent with previous evidence of more limited Notch activation in pancreatic cancer-associated fibroblasts and suggests a primary role for fibroblasts in providing Notch ligand (JAG1) to neighboring cells. In contrast, inhibition of myeloid-specific Notch activation resulted in smaller orthotopic tumors and slowed progression in a genetic model of pancreatic neoplasia. These samples had reduced overall macrophage infiltration, and a secondary alteration of the fibroblast phenotypes was also seen. Collectively, these results suggest that Notch signaling in the myeloid compartment supports tumor progression and regulates multiple components of the pancreatic TME. Future studies will further interrogate how myeloid-specific Notch activation promotes disease progression and affects Notch signaling activation in adjacent compartments. Citation Format: Allison Bischoff, Wei Yan, Carlos Espinoza, Emily Lasse-Opsahl, Nur Renollet, Yaqing Zhang, Marina Pasca di Magliano, Filip Bednar. Deciphering the hierarchy of Notch signaling in the pancreatic tumor microenvironment abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A080.
Bischoff et al. (Sun,) studied this question.