Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an EV- and LXR-dependent manner
Guerman Molostvov,
Mariam Gachechiladze,
Abeer M. Shaaban,
Steven Hayward,
Isaac Dean,
Irundika H.K. Dias,
Nahla Badr,
Irini Danial,
Fiyaz Mohammed,
Vera Novitskaya,
Liliia Paniushkina,
Valerie Speirs,
Andrew Hanby,
Irina Nazarenko,
David R. Withers,
Steven van Laere,
Heather M. Long,
Fedor Berditchevski
Affiliations
Guerman Molostvov
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Mariam Gachechiladze
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Department of Clinical and Molecular Pathology, Palacky Univerzity, 7779 00 Olomouc, Czech Republic
Abeer M. Shaaban
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Steven Hayward
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Isaac Dean
Institute of Immunology and Immunotherapy, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Irundika H.K. Dias
Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK
Nahla Badr
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
Irini Danial
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Fiyaz Mohammed
Institute of Immunology and Immunotherapy, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Vera Novitskaya
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Liliia Paniushkina
Faculty of Medicine, Institute for Infection Prevention and Hospital Epidemiology, Medical Center - University of Freiburg, 79106 Freiburg, Germany
Valerie Speirs
Leeds Institute of Medical Research, University of Leeds, St James’s University Hospital, Leeds LS9 7TF, UK; Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
Andrew Hanby
Leeds Institute of Medical Research, University of Leeds, St James’s University Hospital, Leeds LS9 7TF, UK
Irina Nazarenko
Faculty of Medicine, Institute for Infection Prevention and Hospital Epidemiology, Medical Center - University of Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
David R. Withers
Institute of Immunology and Immunotherapy, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Steven van Laere
Translational Cancer Research Unit Center for Oncological Research, University Antwerp, Antwerp 2610, Belgium
Heather M. Long
Institute of Immunology and Immunotherapy, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
Fedor Berditchevski
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
Summary: The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment of B lymphocytes to BCa tissues is controlled via mechanisms associated with cancer cell-derived extracellular vesicles (CCD-EVs). Gene expression profiling identifies the Liver X receptor (LXR)-dependent transcriptional network as a key pathway that controls both CCD-EVs-induced migration of B cells and accumulation of B cells in BCa tissues. The increased accumulation oxysterol ligands for LXR (i.e., 25-hydroxycholesterol and 27-hydroxycholesterol) in CCD-EVs is regulated by the tetraspanin 6 (Tspan6). Tspan6 stimulates the chemoattractive potential of BCa cells for B cells in an EV- and LXR-dependent manner. These results demonstrate that tetraspanins control intercellular trafficking of oxysterols via CCD-EVs. Furthermore, tetraspanin-dependent changes in the oxysterol composition of CCD-EVs and the LXR signaling axis play a key role in specific changes in the tumor immune microenvironment.
