TY - JOUR
T1 - Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma
AU - Ray, Arja
AU - Callaway, Mackenzie K.
AU - Rodríguez-Merced, Nelson J.
AU - Crampton, Alexandra L.
AU - Carlson, Marjorie
AU - Emme, Kenneth B.
AU - Ensminger, Ethan A.
AU - Kinne, Alexander A.
AU - Schrope, Jonathan H.
AU - Rasmussen, Haley R.
AU - Jiang, Hong
AU - DeNardo, David G.
AU - Wood, David K.
AU - Provenzano, Paolo P.
N1 - Funding Information:
PPP and this work was supported by a Research Scholar Grant (RSG-14-171-01-CSM) from the American Cancer Society and by the NIH (R01CA245550 to DKW and PPP, R01CA181385 to PPP, and U54CA210190 University of Minnesota Physical Sciences in Oncology Center, Project 2 to PPP and Core 1 to DKW). This work was also supported by the Randy Shaver Research and Community Fund (PPP), Masonic Cancer Center (PPP), a University of Minnesota Doctoral Dissertation Fellowship (AR), and grants from the UMN Institute for Engineering in Medicine (PPP and DKW). AR is currently supported by a Cancer Research Institute Postdoctoral Fellowship (CRI2940). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. The authors thank members of the Provenzano laboratory for insightful comments regarding this work.
Publisher Copyright:
Copyright: © 2022, Ray et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/2/8
Y1 - 2022/2/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124436891&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.150330
DO - 10.1172/jci.insight.150330
M3 - Article
C2 - 34914633
AN - SCOPUS:85124436891
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 3
M1 - e150330
ER -