Vucic, E. | bioRxiv Science

bioRxiv2021

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

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

cancer biology↗

bioRxiv2021

Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycans, such as CA-19-9, are biomarkers of PDA and are emerging as important modulators of cancer phenotypes. Herein, we utilized a systems-based approach integrating glycomic analysis of human PDA and the well-established KC mouse model, with transcriptomic data to identify and probe the functional significance of aberrant glycosylation in pancreatic cancer. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of -2,3- and -2,6-sialic acids, bisecting GlcNAc and poly-LacNAc. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes can be modeled in the KC mouse. In silico a nalysis of bulk and single cell sequencing data identified ST6GAL1, which underlies -2,6-sialic acid, as overexpressed in human PDA, concordant with histological data. Enzymes levels correlated with the stage of clinical disease. To test whether ST6GAL1 promotes pancreatic cancer we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. Analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer. SIGNIFICANCEPancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycosylation is emerging as an important modulator of cancer phenotype. Herein we use a systems-approach integrating glycomics of human PDA and a well-established PDA mouse model with transcriptomic data to identify ST6GAL1, the enzyme underlying -2,6-sialic acid, as a potential cancer promoter. A pancreatic specific ST6GAL1 knockout in the KC mouse showed delayed cancer formation and a reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.

cancer biology↗