The robust desmoplasia of PDA is its distinguishing feature and non-malignant components constitute the bulk of the tumor mass. This stromal reaction includes myofibroblasts, inflammatory fibroblasts, endothelial cells, pericytes, and various immune-cell subsets, all embedded within a dense and complex extracellular matrix (ECM). Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with, or coopt the surrounding cells and signaling processes in its microenvironment. It is proposed that an invasive PDA represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster tumorigenesis. The detailed kinetics and stepwise construction of the pancreas cancer neo-organ suggest that it is governed by a discrete set of organizing rules and principles – and repeated attempts to target its specific components reveal self-regulating mechanisms of resistance. Indeed, many of these cells arise and operate at the behest of oncogenic KRAS, the signature genetic mutation in PDA. These cells, in turn, support and shape the evolving malignancy. It is frequently debated in pancreas and other cancers whether the stroma is “good” or “bad”, tumor-constraining or tumor-promoting. However, because the stroma is neither static nor monolithic, the question is misguided. The stroma is more nuanced: some elements overtly accelerate, and others attenuate, disease progression but most of the cells and processes found in an evolving pancreas cancer are adaptive at some point during its development. In the end, these elements collectively conspire to create a drug- and immune-privileged sanctuary for PDA progression. To fully overcome the extraordinary resistance of this formidable cancer will require parsing the myriad interactions and interdependencies among the various stromal elements and the epithelial PDA cell. Understanding how to combine strategies against these distinct components and processes – which ones to target, in what order and for how long – will be critical, and perhaps necessary, for success and to avoid making matters worse.

Citation Format: Sunil R. Hingorani. Stromal-epithelial co-evolution and complicity in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA019.