Abstract 1254: Neural-like progenitor pancreatic cancer cells are enriched in residual disease following neoadjuvant chemoradiotherapy and acquire invasive and stem-like features through inflammatory reprogramming

Abstract Pancreatic ductal adenocarcinoma (PDAC) is notable for a high rate of recurrence and metastasis despite intensive multi-agent chemoradiation. We previously identified a neural-like progenitor (NRP) transcriptional program strongly enriched in PDAC specimens with neoadjuvant chemoradiation and correlated with improved response to therapy. However, the mechanisms for why malignant cells in the post-treatment setting had collectively increased expression of NRP transcriptional signatures remained unclear. In this study, we sought to understand the contexts in which NRP becomes expressed as well as phenotypic effects of NRP genes that may contribute to cancer recurrence. Here, we profile NRP signature expression in human and mouse PDAC model systems, finding that NRP signatures are strongly enriched in regenerative stages of the murine pancreas post-injury, both in oncogene transformed and wild type pancreata. We provide additional evidence that NRP is expressed by a stressed stem-like ductal progenitor population in normal human pancreata and a DCLK1 expressing cancer cell population with undifferentiated cellular morphology in patient tumors. Using 1000-plex whole slide spatial transcriptomic profiling, we identify microenvironmental features associated with NRP cells and propose an inflammatory niche that maintains NRP expression in vivo, that is lost upon in vitro monoculture. Spatial colocalization analysis nominated inflammatory CAFs and IL1B+ macrophage populations as producers of inflammatory factors that upregulate NRP genes. We find that cells utilizing the NRP program have increased reliance on transcription factors involved in pancreatic development and identify Glis3 as a transcription factor highly expressed in NRP cells. We establish isogenic KP (KrasG12D/+;Trp53FL/FL) murine organoid overexpression models using Gata6 and dNTrp63 for the established classical and basal-like PDAC cell states, as well as Glis3. Notably, we find that Glis3 isogenic organoids have markedly higher metastatic proclivity in the orthotopic transplant setting, greater colony formation capacity, and increased invasive and migratory index relative to Gata6 and dNTrp63 driven isogenic models. Glis3 is enriched in matched human PDAC metastases relative to the primary tumor and is also strongly enriched in human cell lines with high metastatic rate in MetMap. Our work deepens understanding of the neural-like progenitor cell state, and particularly the role of developmental transcription factor GLIS3, which is emergent following cytotoxic chemoradiation. Furthermore, we highlight how treatment induced inflammation and tissue injury in the tumor microenvironment contribute to cellular reprogramming that can lead to cancer recurrence and metastasis in the post-treatment setting. Citation Format: Dennis Gong, Jimmy A. Guo, Jennifer Su, Sueda Cetinkaya, Peter Wang, Ashley Lam, Carina Shiau, Laleh Abbassi, Seema Chugh, Andrew J. Aguirre, William L. Hwang. Neural-like progenitor pancreatic cancer cells are enriched in residual disease following neoadjuvant chemoradiotherapy and acquire invasive and stem-like features through inflammatory reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1254.