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      Spatial proximity to fibroblasts impacts molecular features and therapeutic sensitivity of breast cancer cells influencing clinical outcomes

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          Abstract

          Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAFs). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2 + breast cancer cells to lapatinib both in vitro and in vivo including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2 + breast tumors lead to a significant increase of phospho-STAT3 + cancer cells and a decrease in the spatial proximity of proliferating (Ki67 +) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance.

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          Author and article information

          Journal
          2984705R
          2786
          Cancer Res
          Cancer Res.
          Cancer research
          0008-5472
          1538-7445
          21 February 2017
          26 September 2016
          15 November 2016
          15 November 2017
          : 76
          : 22
          : 6495-6506
          Affiliations
          [1 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
          [2 ]Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
          [3 ]BBS Program, Harvard Medical School, Boston, MA 02115, USA
          [4 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
          [5 ]Children's Hospital, Boston, MA 02115, USA
          [6 ]Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045 USA
          [7 ]Thomson Reuters Healthcare & Science, Encinitas, CA 92024, USA
          [8 ]Massachusetts General Hospital, Boston, MA 02114, USA
          [9 ]Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA
          [10 ]Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
          [11 ]Lester and Sue Smith Breast Center and the Dan L Duncan Comprehensive Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
          [12 ]Broad Institute, Cambridge, MA 02138, USA
          Author notes
          Corresponding author: Kornelia Polyak, Dana-Farber Cancer Institute, 450 Brookline Avenue, D740C, Boston, MA 02215, USA. Phone: 617-632-2106; Fax: 617-582-8490; Kornelia_polyak@ 123456dfci.harvard.edu ; Andriy Marusyk, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA. Phone: 813-745-6818; Fax: 813-745-6497; andriy.marusyk@ 123456moffitt.org
          [13]

          Current Affiliation: Moffitt Cancer Center, Tampa, FL 33612

          [*]

          These authors contributed equally to this study.

          [#]

          Current address: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

          Article
          PMC5344673 PMC5344673 5344673 nihpa827016
          10.1158/0008-5472.CAN-16-1457
          5344673
          27671678
          5f8be948-5144-447e-95c4-cfb33dc4fa4f
          History
          Categories
          Article

          lapatinib resistance,breast cancer,microenvironment
          lapatinib resistance, breast cancer, microenvironment

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