Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential

Abstract

Extensive desmoplasia is a prominent feature of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Initially, studies demonstrated that desmoplasia promotes proliferation, invasion and chemoresistance in PDAC cells. While these findings suggested the therapeutic potential of targeting desmoplasia in PDAC, more recent studies utilizing genetically-engineered mouse models of PDAC, which lack key components of desmoplasia, demonstrated accelerated progression of PDAC. This contrast calls into question the paradigm that desmoplasia unilaterally promotes PDAC progression and the premise of desmoplasia-targeted therapy. This review briefly examines the major reports of the tumor-promoting and -restraining roles of desmoplasia in PDAC with commentary on the gaps in our current understanding of desmoplasia in PDAC. Additionally, we discuss the studies demonstrating the heterogeneous and multifaceted nature of desmoplasia in PDAC and advocate for future areas of research to thoroughly address the various facets of desmoplasia in PDAC, reconcile seemingly contradictory reports of the role of desmoplasia in PDAC progression, and discover aspects of desmoplasia that are therapeutically actionable.

Keywords: SHH; cancer-associated fibroblast; desmoplasia; extracellular matrix; pancreatic ductal adenocarcinoma.

Figure 1. Schematic representation of the origin and role of the desmoplastic reaction in PDAC progression

Cancer cells secrete multiple factors including SHH, FGF2, TGFβ1, and PDGF that result in CAF proliferation, recruitment of CAF precursors, and activation of CAFs. Activated CAFs, in turn, secrete factors that promote the proliferation, invasion, migration and metastatic features of PDAC cells. In addition, activated CAFs secrete immunosuppressive cytokines and components of extracellular matrix (ECM), obstructing tumor perfusion and developing the hypoxic environment. The dense ECM further contributes to PDAC progression through contact-mediated lymphocyte trapping and stimulation of Integrin/FAK signaling in PDAC cells.

Figure 2. Model of CAF heterogeneity in PDAC

A. Based on the phenotypic characteristics, inflammatory (α-SMA low, FAP high) and myofibroblast (α-SMA high, FAP low) CAF subsets exist in a dynamic equilibrium during tumor progression. The crosstalk and secretome of the heterogeneous CAF populations create a unique microenvironment affecting infiltrating immune cells, tumor vasculature and cancer cells that dictate their dichotomous role during early and late phases of tumor development. B. Depletion of the myofibroblasts subset allows the predominance of inflammatory CAFs in the TME leading to suppression of anti-tumor immune response, reduced ECM deposition and angiogenesis as well as a poorly differentiated cancer cell phenotype.