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@ARTICLE{Fan:289227,
      author       = {G. Fan and B. Yu and L. Tang and R. Zhu and J. Chen and Y.
                      Zhu and H. Huang and L. Zhou and J. Liu and W. Wang and Z.
                      Tao and F. Zhang and S. Yu and X. Lu and Y. Cao and S. Du
                      and H. Li and J. Li and J. Zhang and H. Ren and O. Gires and
                      H. Liu$^*$ and X. Wang and J. Qin and H. Wang},
      title        = {{TSPAN}8+ myofibroblastic cancer-associated fibroblasts
                      promote chemoresistance in patients with breast cancer.},
      journal      = {Science translational medicine},
      volume       = {16},
      number       = {741},
      issn         = {1946-6234},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DKFZ-2024-00661},
      pages        = {eadj5705},
      year         = {2024},
      abstract     = {Cancer-associated fibroblasts (CAFs) are abundant stromal
                      cells in the tumor microenvironment that promote cancer
                      progression and relapse. However, the heterogeneity and
                      regulatory roles of CAFs underlying chemoresistance remain
                      largely unclear. Here, we performed a single-cell analysis
                      using high-dimensional flow cytometry analysis and
                      identified a distinct senescence-like tetraspanin-8
                      (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is
                      correlated with therapeutic resistance and poor survival in
                      multiple cohorts of patients with breast cancer (BC).
                      TSPAN8+ myCAFs potentiate the stemness of the surrounding BC
                      cells through secretion of senescence-associated secretory
                      phenotype (SASP)-related factors IL-6 and IL-8 to counteract
                      chemotherapy. NAD-dependent protein deacetylase sirtuin 6
                      (SIRT6) reduction was responsible for the senescence-like
                      phenotype and tumor-promoting role of TSPAN8+ myCAFs.
                      Mechanistically, TSPAN8 promoted the phosphorylation of
                      ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6)
                      at Ser772 by recruiting MAPK11, thereby inducing SIRT6
                      protein destruction. In turn, SIRT6 down-regulation
                      up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to
                      secrete aspartate and proline, and therefore proved a
                      nutritional niche to support BC outgrowth. By demonstrating
                      that TSPAN8+SIRT6low myCAFs were tightly associated with
                      unfavorable disease outcomes, we proposed that the combined
                      regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800
                      is a promising approach to overcome chemoresistance. These
                      findings highlight that senescence contributes to CAF
                      heterogeneity and chemoresistance and suggest that targeting
                      TSPAN8+ myCAFs is a promising approach to circumvent
                      chemoresistance.},
      cin          = {A240},
      ddc          = {500},
      cid          = {I:(DE-He78)A240-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38569015},
      doi          = {10.1126/scitranslmed.adj5705},
      url          = {https://inrepo02.dkfz.de/record/289227},
}