The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

SIMPLE SUMMARY: Pancreatic cancer is a highly malignant disease with treatment resistance to standardized chemotherapies. In addition, only a small fraction of patients with pancreatic cancer has, to date, actionable genetic aberrations, leading to a narrow therapeutic window for molecularly targeted therapies or immunotherapies. A lot of preclinical and translational studies are ongoing to discover potential vulnerabilities to treat pancreatic cancer. Histologically, human pancreatic cancer is characterized by abundant cancer-associated fibrotic stroma, called “desmoplastic stroma”. Recent technological advances have revealed that desmoplastic stroma in pancreatic cancer is much more complicated than previously thought, playing pleiotropic roles in manipulating tumor cell fate and anti-tumor immunity. Moreover, real-world specimen-based analyses of pancreatic cancer stroma have also uncovered spatial heterogeneity and an intertumoral variety associated with molecular alterations, clinicopathological factors, and patient outcomes. This review describes an overview of the current efforts in the field of pancreatic cancer stromal biology and discusses treatment opportunities of stroma-modifying therapies against this hard-to-treat cancer. ABSTRACT: Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.