Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Abstract

Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

Fig. 1

PDAC initiation and establishment of desmoplastic stroma. The desmoplastic stroma typically precedes and co-evolves with neoplastic progression in PDAC. The stroma is characterized by diverse cellular and non-cellular components that undergo constant remodeling in response to tumor progression and therapeutic intervention. In addition to intrinsic genetic mutations, a subset of PDAC cells engage the EMT program under stromal clues and metastasize

Fig 2

Collective contribution of CAFs and immune cells to EMT. CAFs interact with both the tumor cells and immune cells especially M2 TAMs through secreted cytokines and chemokines, resulting in PDAC EMT

Fig 3

Role of TGF-β, IL-6, and IL-1β signaling pathways in PDAC EMT. a TGF-β signaling pathway can be SMAD-dependent or independent. In SMAD-dependent setting, TGF-β binds its receptor complex (TGF-β receptors I/II dimer) and phosphorylate SMAD proteins and subsequently transported into the nucleus to induce EMT-TFs. Activation of TGFR can also engage MAPK and NF-kB signaling to transactivate EMT-TFs. b Engagement of the IL-6R activates JAK kinases which phospho-activate STAT3 transcription factor, leading to upregulation of EMT-TFs. c Activation of IL-1R engages IRAK4-TAK1 and the downstream NF-κB, JNK, and p38 MAPK cascades to promote EMT

Fig. 4

Summary of advantages and limitations of currently available preclinical models of PDAC. Desmoplastic stroma is a typical characteristic of pancreatic cancer tumor microenvironment that promote epithelial-to-mesenchymal transition (EMT) and therapeutic resistance. Improvement of in vitro models that include stromal cells including CAFs and immune cells should be increasingly incorporated to identify therapeutic strategies that can be further tested in mouse models