title: Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer.
abstract: Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2(+) breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system xc(-), as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lanzardo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Conti
authors.affiliation: Elsalys Biotech, Illkirch Graffenstaden, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Rooke
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ruiu
authors.affiliation: Novartis Institute for Medical Research, Basel, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Accart
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolli
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Arigoni
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macagno
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.affiliation: Takis, Via di Castel Romano, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurisicchio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Raffaele Adolfo
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy. federica.cavallo@unito.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
mesh_terms: D026905:Amino Acid Transport Systems / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003553:Cystine / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D018698:Glutamic Acid / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D026905:Amino Acid Transport Systems; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D019444:Vaccines, DNA; D018698:Glutamic Acid; D003553:Cystine