title: MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer.
abstract: Communication between cancer cells and the tumor microenvironment results in the modulation of complex signaling networks that facilitate tumor progression. Here, we describe a new mechanism of intercellular communication originating from large oncosomes (LO), which are cancer cell-derived, atypically large (1-10 μm) extracellular vesicles (EV). We demonstrate that, in the context of prostate cancer, LO harbor sustained AKT1 kinase activity, nominating them as active signaling platforms. Active AKT1 was detected in circulating EV from the plasma of metastatic prostate cancer patients and was LO specific. LO internalization induced reprogramming of human normal prostate fibroblasts as reflected by high levels of α-SMA, IL6, and MMP9. In turn, LO-reprogrammed normal prostate fibroblasts stimulated endothelial tube formationin vitroand promoted tumor growth in mice. Activation of stromal MYC was critical for this reprogramming and for the sustained cellular responses elicited by LO, bothin vitroandin vivoin an AKT1-dependent manner. Inhibition of LO internalization prevented activation of MYC and impaired the tumor-supporting properties of fibroblasts. Overall, our data show that prostate cancer-derived LO powerfully promote establishment of a tumor-supportive environment by inducing a novel reprogramming of the stroma. This mechanism offers potential alternative options for patient treatment.Cancer Res; 77(9); 2306-17. ©2017 AACR.
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Valentina R
authors.initials: VR
authors.lastname: Minciacchi
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Spinelli
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Mariana
authors.initials: M
authors.lastname: Reis-Sobreiro
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.|Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cavallini
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Mandana
authors.initials: M
authors.lastname: Zandian
authors.affiliation: Van Andel Institute, Grand Rapids, Michigan.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.|Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: The Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
authors.affiliation: Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viglietto
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.|The Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts.|Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cocucci
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Bhowmick
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. dolores.divizio@cshs.org.|The Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts.|Department of Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000235:genetics*; D000067128:Extracellular Vesicles / Q000235:genetics / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000097:blood / Q000235:genetics*; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt