Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

SIMPLE SUMMARY: There is currently no effective treatment for Pancreatic Ductal Adenocarcinoma (PDAC), and it is still the deadliest cancer, despite great research efforts in recent decades. The complexity in the tumor microenvironment (TME) is one of the main roots for the refractory nature of PDAC to treatment. Components of the PDAC TME are complex, dynamic, and closely reciprocate with each other from the early stages of pre-neoplastic lesion and during tumor progression. Detailed insight of the PDAC tumor microenvironment is needed for developing combined therapeutics that would target cancer cells and their supportive milieu for more efficient PDAC treatment. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.