title: Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.
abstract: The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhifeed-forward loop responsible for the generation of CD133hiCSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hiCAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led tode novoHTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hicells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hiCSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promotedde novoHT resistance via the generation of CD133hiCSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control.Cancer Res; 77(8); 1927-41. ©2017 AACR.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Sansone
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marjan
authors.initials: M
authors.lastname: Berishaj
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vinagolu K
authors.initials: VK
authors.lastname: Rajasekhar
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Biological, Geological and Environmental Sciences, Università di Bologna, Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Strillacci
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy.|Center for Applied Biomedical Research Laboratory, Policlinico Universitario S. Orsola-Malpighi AlmaMater Studiorum, Università di Bologna, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Savini
authors.affiliation: Department of Radiation Oncology, Kaiser Permanente, Oakland, California.
authors.forename: Lauren
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mastroleo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy.|Center for Applied Biomedical Research Laboratory, Policlinico Universitario S. Orsola-Malpighi AlmaMater Studiorum, Università di Bologna, Bologna, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: De Carolis
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Daly
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medicine, New York, New York.
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito-Martin
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.affiliation: Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fabbri
authors.affiliation: Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Università di Bologna, Bologna, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Spisni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cricca
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medicine, New York, New York.|Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy.|Department of Radiation Oncology, Kaiser Permanente, Oakland, California.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafé
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. bromberj@mskcc.org.|Department of Medicine, Weill Cornell Medicine, New York, New York.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000072645:Cancer-Associated Fibroblasts; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004958:Estradiol; D000077267:Fulvestrant; D015850:Interleukin-6; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C508600:IL6 protein, human; C525709:MIR221, human; C494086:STAT3 protein, human