Multiphasic Heterogeneity of Fibroblasts in the Microenvironment of Pancreatic Ductal Adenocarcinoma: Dissection and the Sum of the Dynamics

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, characteristically exhibits abundant stroma, including marked fibrosis in the tumor microenvironment, which is considered highly associated with its crucial malignant potential and extremely poor prognosis. To conquer PDAC, it is vital to understand the microenvironment in detail. In this Special Issue, “Tumor Microenvironment and Pancreatic Cancer”, various aspects of microenvironment are discussed: heterogeneity of cancer-associated fibroblasts (CAFs), including possible cancer-promoting and -restraining properties, the significance of the extracellular matrix (ECM) and targeting ECM components, the dynamics of the immune microenvironment, metabolic property of PDAC cells in the tumor microenvironment, the association of the PDAC microenvironment and microbiome, as well as neural signaling, and the effect of anesthetic drugs on PDAC. This evidence indicates that the PDAC microenvironment is more complicated than expected. The suggested multiphasic diversity and heterogeneity of the PDAC microenvironment may be a consequence of the sum of more transient change and dynamic plasticity through various tumor–stromal interactions. ABSTRACT: Pancreatic cancer is still the most intractable cancer, with a 5-year survival of around 10%. To conquer the most common type, pancreatic ductal adenocarcinoma (PDAC), we need to understand its pathobiology, especially the tumor microenvironment (TME) that characteristically contains abundant stromal components, with marked fibrosis. In this Special Issue, “Tumor Microenvironment and Pancreatic Cancer”, various aspects of TME were discussed, most frequently including articles related to cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM). CAFs and ECM have been considered in favor of PDAC cells; however, surprisingly, depleting CAFs or reducing the stromal components in PDAC-model mice induced aggressive PDAC and worsened the prognosis. Subsequently, accumulating studies have elucidated evidence of the heterogeneity of CAFs and the plasticity between the subtypes. Possible cancer-promoting and -restraining properties of the CAF subtypes have been suggested, but these are yet to be fully elucidated. Here, in addition to the extensive reviews on the heterogeneity of CAFs in this Special Issue, I refer to another insight from a recent integrative study of PDAC TME, that PDAC TME can be divided into three distinct sub-tumor microenvironments (subTMEs), and the co-existence of the distinct subTMEs is associated with poor prognosis. In the subTME, the heterogeneity of each component, including CAFs, can be changed transiently through various interactions in the TME, and the sum of the transient change and dynamic plasticity might be timely tuned in the co-existence of distinct subTMEs to contribute to the poor prognosis. Thus, understanding the more detailed underlying mechanisms in this heterogeneity of TME, as well as how to control the sum of multiphasic heterogeneity, might lead to the establishment of a more desirable therapeutic strategy to conquer intractable PDAC.