Article ; Online: Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma.
JCI insight
2022 Volume 7, Issue 3
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 ...
| 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. |
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| MeSH term(s) | Animals ; Apoptosis ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Pancreatic Ductal/therapy ; Cell Line, Tumor ; Cell Movement ; Focal Adhesion Kinase 1/antagonists & inhibitors ; Focal Adhesion Kinase 1/biosynthesis ; Focal Adhesion Kinase 1/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Transgenic ; Neoplasms, Experimental ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/therapy ; RNA, Small Interfering/genetics ; Tumor Microenvironment/genetics |
| Chemical Substances | RNA, Small Interfering ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; Ptk2 protein, mouse (EC 2.7.10.2) |
| Language | English |
| Publishing date | 2022-02-08 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ISSN | 2379-3708 |
| ISSN (online) | 2379-3708 |
| DOI | 10.1172/jci.insight.150330 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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