Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine
Singh, K.; Faraoni, E. Y.; Dai, Y.; Chandra, V.; Vucic, E.; Mills, T.; Pruski, M.; Clark, T.; Van Buren, G.; Thosani, N. C.; Bynon, J. S.; Wray, C. J.; Bar-Sagi, D.; Poulsen, K. L.; Vornik, L. A.; Savage, M. I.; Sei, S.; Mohammed, A.; Zhao, Z.; Eltzschig, H. K.; Brown, P. H.; McAllister, F.; Bailey Lundberg, J.
Show abstract
The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/470415v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@14625org.highwire.dtl.DTLVardef@1a43372org.highwire.dtl.DTLVardef@12dc0c8org.highwire.dtl.DTLVardef@cbb835_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress 97%
- Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice 94%
- Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis 93%
Similar papers in this journal
- Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts 97%
- Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblastdriven nutritional support and immunosuppression 97%
- Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.