Pancreatic Ductal Adenocarcinoma Tumor Suppressors Rgs8–16

G protein‐coupled receptors (GPCRs) are the largest family of targets for approved drugs, but rarely exploited in cancer treatment. Kras oncogenic mutations (e.g. KrasG12D) are found in over 90% of human pancreatic ductal adenocarcinoma (PDA) and can be activated by protein kinases and GPCR signaling. Regulator of G protein signaling (Rgs) proteins modulate GPCR signaling by accelerating the GTPase activity of Gq‐ and Gi‐class alpha subunits. Rgs genes are often upregulated in primary cancers. We showed that Rgs8::GFP and Rgs16::GFP reporter genes are highly expressed in an oncogenic Kras (Kras G12D )‐dependent PDA model at initiation and throughout progression. Furthermore, activating alleles of Gq that are resistant to Rgs inhibition are found in benign precursors of PDA in humans. By contrast, Rgs16 down‐regulation is associated with increased lymph node metastasis in PDA. Here we test our hypothesis that Rgs8–16 deletion will accelerate PDA initiation, progression, and metastasis. Methods We made the Rgs8–16 double knockout (dKO) and crossed it into pancreas‐specific Kras G12D (KC) mutant mice (termed KCR8–16). Caerulein (analog of the Gq‐coupled GPCR agonist CCK) induced acute and chronic pancreatitis, PDA initiation and progression. Response to caerulein was compared in KC and KCR8–16 mice using physiologic, histologic and immunologic assays. Results Caerulein induced Rgs16 expression in acute pancreatitis within 2 days in Rgs16::GFP transgenic mice, and they recovered normally within 7days. Although deletion of Rgs8–16 did not cause PDA initiation, Rgs8–16 dKO mice took longer to recover from caerulein‐induced pancreatitis than normal mice. PDA initiation and progression was greatly accelerated in KCR8–16 compared to KC mice. Caerulein treatment caused the entire pancreas to transform to aggressive PDA within 7 days in KCR8–16 mice, whereas KC pancreata showed milder acinar‐to‐ducal metaplasia and differentiated, early stage PDA. Cell proliferation and epithelial‐to‐mesenchymal transmission (EMT) was amplified in KCR8–16 mice, with increased Ki67 and EMT marker expression, suggesting a greater potential for metastasis. Discussion We find Rgs8 and Rgs16 are tumor suppressors in PDA initiation and progression. Little is known about GPCR expression and function in PDA. Few GPCR‐targeted therapeutics exist for PDA. The KCR8–16 and Rgs16::GFP mice we developed provide excellent models for screening ligands to identify GPCRs involved in PDA initiation and progression. KCR8–16 hypersensitivity to Gq‐coupled ligands provides a model for rapid in vivo validation of PDA therapeutics. Support or Funding Information This work supported by NCI CA161624 and UT Southwestern Cancer Center Pilot Project Award to RAB and TMW This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .