title: Modeling synovial sarcoma metastasis in the mouse: PI3'-lipid signaling and inflammation.
abstract: Solid tumor metastasis is a complex biology, impinged upon by a variety of dysregulated signaling pathways. PI3'-lipid signaling has been associated with metastasis and inflammation in many cancers, but the relationship between tumor cell-intrinsic PI3'-lipid signaling and inflammatory cell recruitment has remained enigmatic. Elevated PI3'-lipid signaling associates with progression of synovial sarcoma, a deadly soft tissue malignancy initiated by a t(X;18) chromosomal translocation that generates an SS18-SSX fusion oncoprotein. Here, we show in genetically engineered mouse models of locally induced expression of SS18-SSX1 or SS18-SSX2 that Pten silencing dramatically accelerated and enhanced sarcomagenesis without compromising synovial sarcoma characteristics. PTEN deficiency increased tumor angiogenesis, promoted inflammatory gene expression, and enabled highly penetrant spontaneous pulmonary metastasis. PTEN-deficient sarcomas revealed infiltrating myeloid-derived hematopoietic cells, particularly macrophages and neutrophils, recruited via PI3'-lipid-induced CSF1 expression in tumor cells. Moreover, in a large panel of human synovial sarcomas, enhanced PI3'-lipid signaling also correlated with increased inflammatory cell recruitment and CSF1R signal transduction in both macrophages and endothelial cells. Thus, both in the mouse model and in human synovial sarcomas, PI3'-lipid signaling drives CSF1 expression and associates with increased infiltration of the monocyte/macrophage lineage as well as neutrophils.
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Jared J
authors.identifier: 0000-0001-6059-9009
authors.initials: JJ
authors.lastname: Barrott
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.
authors.forename: Lisa A
authors.identifier: 0000-0002-8181-2726
authors.initials: LA
authors.lastname: Kafchinski
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Potter
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Sarmishta D
authors.initials: SD
authors.lastname: Kannan
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Robert
authors.identifier: 0000-0002-4602-1240
authors.initials: R
authors.lastname: Kennedy
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.|Department of Bioinformatics, University of Utah, Salt Lake City, UT 84112.
authors.forename: Tim
authors.identifier: 0000-0002-7676-7465
authors.initials: T
authors.lastname: Mosbruger
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Wei-Lien
authors.identifier: 0000-0001-8809-4424
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Tsai
authors.affiliation: Sarcoma Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Dejka M
authors.initials: DM
authors.lastname: Araujo
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.|Department of Pathology, University of Utah, Salt Lake City, UT 84112.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 84112.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Alexander J
authors.identifier: 0000-0002-6395-4499
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112 kevin.jones@hci.utah.edu.|Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Kevin B
authors.identifier: 0000-0003-1531-2157
authors.initials: KB
authors.lastname: Jones
mesh_terms: D000818:Animals; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C501211:Ss18 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse