Pruski, M. | Search bioRxiv

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↗

bioRxiv2020

Glioblastoma Cell Migration is Directed by Electrical Signals

BackgroundElectric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signaling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPAR{gamma}) agonists. We investigated the effect of electric fields on GBM differentiated and stem cell migration and whether this was affected by treatment with the PPAR{gamma} agonist pioglitazone. MethodsPrimary GBM cell lines were cultured as differentiated and glioma stem cells (GSCs) and then exposed to EFs using electrotaxis chambers and imaged with time lapse microscopy. Cells were then treated with varying concentrations of pioglitazone and/or its inhibitor GW9662 and their responses to EFs examined. ResultsWe demonstrated that GBM differentiated and GSCs have opposing preferences for anodal and cathodal migration, respectively. Pioglitazone treatment resulted in significantly decreased directed cell migration in both cell types. Western blot analysis did not demonstrate any change in PPAR{gamma} expression with and without exposure to EF. ConclusionsOpposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.

cancer biology↗