A novel GPCR mediates pancreatic cancer associated fibroblast-cancer cell interaction

Shu Z WILEY,Krishna SRIRAM,Wen-jing LIANG,Sarah E CHANG,Randall FRENCH,Thalia MCCANN,Hiroshi NISHIHARA,Andrew M LOWY,Paul A INSEL.

(1.Departments of Pharmacology,Medicine and Surgery and Moores Cancer Center,University of California,San Diego La Jolla,CA 92093;2.Division of Clinical Cancer Genomics,Hokkaido Cancer Center,Shiroishi-ku,Sapporo,Japan)

T1-5

A novel GPCR mediates pancreatic cancer associated fibroblast-cancer cell interaction

Shu Z WILEY1,Krishna SRIRAM1,Wen-jing LIANG1,Sarah E CHANG1,Randall FRENCH1,Thalia MCCANN1,Hiroshi NISHIHARA2,Andrew M LOWY1,Paul A INSEL1.

(1.Departments of Pharmacology,Medicine and Surgery and Moores Cancer Center,University of California,San Diego La Jolla,CA 92093;2.Division of Clinical Cancer Genomics,Hokkaido Cancer Center,Shiroishi-ku,Sapporo,Japan)

OBJECTIVEPancreatic 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 RESULTSHypothe?sizing that Gprotein-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 aGPCR 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 interleukin-6(IL-6)via a cAMP/PKA/CREB signaling pathway.GPCR knockdown with siRNA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells.CONCLUSIONWe 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.

pancreatic ductal adenocarcinoma;pancreatic cancer-associated fibroblasts;Gproteincoupled receptors