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

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.

Molecular underpinnings of pancreatic cancer: Innovations in treatment and future perspectives

“…Tailoring therapies to individual patients' molecular profiles is a complex task. [48] Tumor microenvironment: The pancreatic tumor microenvironment plays a critical role in disease…”

Significance of Tumor Microenvironment for Regulating Pancreatic Cancer

“…In this Special Issue, CAFs and the extracellular matrix (ECM), impressive features of the PDAC TME, were the most frequently reviewed and discussed [28][29][30][31][32][33][34]. Functional heterogeneity of CAF subtypes was repeatedly described: some might be tumor-promoting, while others might be tumor-suppressive.…”

“…Heger et al analyzed the PDAC stroma after neoadjuvant chemotherapy (NAC) and documented a better prognosis of the patients with low α-smooth muscle actin density, suggesting a difference from the patients who underwent upfront surgery [33]. Ijichi also discussed the CAF heterogeneity along with the prognostic significance of the sub-tumor microenvironment (subTME), a combination of CAF subtypes and various immune-inflammatory infiltrates as well as ECM [34].…”