title: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.
abstract: Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely noncoding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent antiviral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate crosstalk with BrCa cells by utilizing exosomes to instigate antiviral signaling. This expands BrCa subpopulations adept at resisting therapy and reinitiating tumor growth.
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mirjam C
authors.initials: MC
authors.lastname: Boelens
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Barzin Y
authors.initials: BY
authors.lastname: Nabet
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bihui
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Taewon
authors.initials: T
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry & Molecular Biology, Braman Family Breast Cancer Institute at Sylvester, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Azzam
authors.affiliation: Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Twyman-Saint Victor
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brianne Z
authors.initials: BZ
authors.lastname: Wiemann
authors.affiliation: Department of Public Health Sciences, Division of Biostatistics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Hemant
authors.initials: H
authors.lastname: Ishwaran
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Petra J
authors.initials: PJ
authors.lastname: Ter Brugge
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Department of Biochemistry & Molecular Biology, Braman Family Breast Cancer Institute at Sylvester, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Slingerland
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: andyminn@exchange.upenn.edu.
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008819:Mice, Nude; D019899:Paracrine Communication; D011836:Radiation Tolerance; D051880:Receptors, Notch / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D050794:STAT1 Transcription Factor; D007372:Interferons; D020691:rab GTP-Binding Proteins