Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma.

Arja Ray,Hong Jiang,David G Denardo,Nelson J Rodríguez-Merced,Mackenzie K Callaway,Paolo P Provenzano,Kenneth B Emme,Ethan A Ensminger,David K Wood,Haley R Rasmussen,Marjorie Carlson,Jonathan H Schrope,Alexander A Kinne,Alexandra L Crampton

doi:10.1172/jci.insight.150330

Abstract

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to reengineer and normalize tumor microenvironments may have roles not only in very early disease, but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma-targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination.

Highlights

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a dismal 5-year survival of ~9% [1]
Consistent with the desmoplastic response associated with PDA, as expected, robust fibrous collagen was ubiquitous in the periductal areas around pancreatic intraepithelial neoplasia (PanIN) lesions, which are histologically well-defined precursors to invasive ductal pancreatic adenocarcinoma (Figure 1, C and E)
It is clear that the deposition and organization of periductal collagen play important roles in the early dissemination and metastasis of PDA and may be used as biomarkers for disease progression, where tumor-associated collagen signatures (TACS)+ findings around histologically “early” disease may indicate more advanced disease than classic histology would suggest and aid the pathology and treatment plan processes

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a dismal 5-year survival of ~9% [1]. Recent studies using an autochthonous mouse model of PDA demonstrate that single carcinoma cells can disseminate into the ECM-rich stroma and peripheral blood even before frank histologically detectable malignancy [11]. This is consistent with early disseminated cancer cells (DCCs) observed in breast cancer [12, 13] and decreased efficiency of dissemination in PDA following treatment with antifibrotic or antiinflammatory agents [7, 11], challenging the concept that metastasis is always a late event in cancer progression. The desmoplastic stroma appears to be a key player in early metastatic cell dissemination, yet the mechanisms by which the fibrotic stroma aids early dissemination are unknown

Methods

Results

Conclusion