title: Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.
abstract: Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-β-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-β signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.|Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Beach
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Paul-Joseph P
authors.initials: PJ
authors.lastname: Aspuria
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Dong-Joo
authors.initials: DJ
authors.lastname: Cheon
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Hasmik
authors.initials: H
authors.lastname: Agadjanian
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Walsh
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Women's Cancer Program at The Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: cancer-associated fibroblast (CAF); microenvironment; sphingosine kinase 1 (SPHK1); sphingosine-1-phosphate (S1P); transforming growth factor-beta 1 (TGF-β1)