Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an EV- and LXR-dependent manner

• DOI: 10.1016/j.celrep.2023.112207
• Publication Date: 2023-03-03T00:30:49Z
• Authors: 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
• Keywords: 570; Supplementary Information; QH301-705.5; Tetraspanins; 610; Breast Neoplasms; R Medicine; breast cancer; SDG 3 - Good Health and Well-being; Tumor Microenvironment; tumor microenvironment; Humans; Wellcome Trust; Biology (General); Biology; Liver X Receptors; B cells; B-Lymphocytes; R; Oxysterols; 3. Good health; tetraspanins; 099266/Z/12/Z; oxysterols; LXR; Female; Human medicine; CP: Cancer

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.