Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma

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.

Tissue-engineered models of lung cancer premalignancy

“…Fibrillar collagen has also been implicated in tumor invasiveness during metastatic transition 33,70 , making collagen dynamics a critical aspect for modeling premalignancy. One limitation of the use of a CGFOGER peptide in our studies is that it lacks the full architecture of fibrillar collagen, which has been proven to both change with and directly promote tumor progression 33,70 . Future studies with hydrogel-embedded PCLS could use hybrid-hydrogels that incorporate decellularized ECM (dECM) containing larger intact proteins and growth factors [71][72][73] .…”

“…Dense fibrillar collagen promotes proliferation of epithelial cells, healthy or cancerous, by activation of integrin-mediated FAK signaling 34,69 . Fibrillar collagen has also been implicated in tumor invasiveness during metastatic transition 33,70 , making collagen dynamics a critical aspect for modeling premalignancy. One limitation of the use of a CGFOGER peptide in our studies is that it lacks the full architecture of fibrillar collagen, which has been proven to both change with and directly promote tumor progression 33,70 .…”

The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights

“…In addition to ECM composition, differences in the organization pattern of adhesion molecules can influence the migratory and invasive abilities of PDAC cells. Both mouse and human PDAC tumors exhibit distinct tumor-associated collagen signatures (TACSs) that are characterized by unique densities, matrix stiffness, and spatial arrangements in relation to the tumor cells [ 189 ]. Using a 3D organoid model, Ray et al demonstrated that specific TACSs facilitate enhanced single-cell invasion of PDAC cells into the surrounding stroma.…”

“…Inhibition of FAK was associated with significantly fewer single-cell extrusions and lung metastases in an in vivo mouse model of the TACS-3 phenotype only. Due to the unique physical properties of each TACS phenotype, these findings underscore a role for FAK as a mechanotransducer [ 189 ].…”

Remodelling of the fibre-aggregate structure of collagen gels by cancer-associated fibroblasts: a time-resolved grey-tone image analysis based on stochastic modelling

“…This collagen accretion increases the stiffness and creates discrete structural patterns called tumor-associated collagen signatures (TACS) in the stroma. These anisotropic patterns promote directed cell migration into and through the stroma by contact guidance [19][20][21][22]. The stroma comprises a complex ecosystem of endothelial cells, immune cells, and cancer-associated fibroblasts (CAFs) [23].…”