OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancreatic cancer-associated fibroblasts(PCAFs)derived from pancreatic stellate cells(PSCs)and pancreatic fibroblasts(PFs).METHEDS and RESULTS Hypothesizing that G protein-coupled receptors(GPCRs)may regulate PCAFs,we used an unbiased GPCRomic array approach to compare GPCR expression in PCAFs,PFs and PSCs and identified 82 GPCRs commonly expressed by PCAFs derived from primary tumors of five PDAC patients.We discovered that PCAFs have increased expression of numerous GPCRs,in particular a GPCR with much higher expression in PCAFs compared to both PFs and PSCs.Immunohistochemistry revealed increased expression of this GPCR in PDAC tumors.Co-culture of PSCs with PDAC cells or incubation with TNFαinduced its expression.Activation of the GPCR in PCAF sincreased expression of interleukin-6(IL-6)via a cA MP/PKA/CREB signaling pathway.GPCR knockdown with siR NA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells.CONCLUSION We conclude that PDAC cells induce expression by PCAFs of a novel GPCR,resulting in increased IL-6 production by PCAFs and promotion of PDAC cell proliferation.This PCAF-expressed GPCR thus contributes to PDAC cell-PCAF interaction and as such,may be a novel therapeutic target for PDAC tumors. OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC), a lethal cancer in need of new, effective therapies, has a unique tumor microenvironment characterized by a dense fibrotic stroma (desmoplasia) that is generated by pancreatic cancer-associated fibroblasts (PCAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). METHEDS and RESULTS Hypothesizing that G protein-coupled receptors (GPCRs) may regulate PCAFs, we used an unbiased GPCRomic array approach to compare GPCR expressions in PCAFs, PFs and PSCs and identified 82 GPCRs frequently expressed by PCAFs derived from primary tumors of five PDAC patients. We discovered that PCAFs have increased expression of numerous GPCRs, in particular a GPCR with much higher expression in PCAFs compared to both PFs and PSCs. Immunohistochemistry revealed increased expression of this GPCR in PDAC tumors. Co-culture of PSCs with PDAC cells or incubation with TNFα induced its expression. Activation of the GPCR in PCAF sincreased expression of interl eukin-6 (IL-6) via a cA MP / PKA / CREB signaling pathway. PCR knockdown with siR NA diminished IL-6 production and secretion by PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells. CONCLUSION We conclude that PDAC cells induce expression by PCAFs of a novel GPCR, resulting in increased IL-6 production by PCAFs and promotion of PDAC cell proliferation. This PCAF-expressed GPCR contributes to PDAC cell-PCAF interaction and as such, may be a novel therapeutic target for PDAC tumors.