Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma
Shamik Mascharak, Jason Guo, Deshka S. Foster, Anum Khan, Michael F. Davitt, Alan Nguyen, Austin Burcham, Malini Chinta, Nicholas Guardino, Michelle Griffin, David M. Lopez, Elisabeth Miller, Michael Januszyk, Shyam S. Raghavan, Teri A. Longacre, Daniel Delitto, Jeffrey A. Norton, Michael T. Longaker
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.