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@ARTICLE{Kocher:289500,
      author       = {D. Kocher$^*$ and L. Cao and R. Guiho and M. Langhammer and
                      Y.-L. Lai$^*$ and P. Becker$^*$ and H. Hamdi and D.
                      Friedel$^*$ and F. Selt$^*$ and D. Vonhören$^*$ and J.
                      Zaman$^*$ and G. Valinciute$^*$ and S. Herter$^*$ and D.
                      Picard$^*$ and J. Rettenmeier$^*$ and K. K. Maass$^*$ and K.
                      W. Pajtler$^*$ and M. Remke and A. von Deimling$^*$ and S.
                      Pusch$^*$ and S. M. Pfister$^*$ and I. Oehme$^*$ and D. T.
                      W. Jones$^*$ and S. Halbach$^*$ and T. Brummer$^*$ and J. P.
                      Martinez-Barbera and O. Witt$^*$ and T. Milde$^*$ and R.
                      Sigaud$^*$},
      title        = {{R}ebound growth of {BRAF} mutant pediatric glioma cells
                      after {MAPK}i withdrawal is associated with {MAPK}
                      reactivation and secretion of microglia-recruiting
                      cytokines.},
      journal      = {Journal of neuro-oncology},
      volume       = {168},
      number       = {2},
      issn         = {0167-594X},
      address      = {Dordrecht [u.a.]},
      publisher    = {Springer Science + Business Media B.V},
      reportid     = {DKFZ-2024-00822},
      pages        = {317-332},
      year         = {2024},
      note         = {#EA:B310#LA:B310# / 2024 Jun;168(2):317-332},
      abstract     = {Patients with pediatric low-grade gliomas (pLGGs), the most
                      common primary brain tumors in children, can often benefit
                      from MAPK inhibitor (MAPKi) treatment. However, rapid tumor
                      regrowth, also referred to as rebound growth, may occur once
                      treatment is stopped, constituting a significant clinical
                      challenge.Four patient-derived pediatric glioma models were
                      investigated to model rebound growth in vitro based on
                      viable cell counts in response to MAPKi treatment and
                      withdrawal. A multi-omics dataset (RNA sequencing and
                      LC-MS/MS based phospho-/proteomics) was generated to
                      investigate possible rebound-driving mechanisms. Following
                      in vitro validation, putative rebound-driving mechanisms
                      were validated in vivo using the BT-40 orthotopic xenograft
                      model.Of the tested models, only a BRAFV600E-driven model
                      (BT-40, with additional CDKN2A/Bdel) showed rebound growth
                      upon MAPKi withdrawal. Using this model, we identified a
                      rapid reactivation of the MAPK pathway upon MAPKi withdrawal
                      in vitro, also confirmed in vivo. Furthermore, transient
                      overactivation of key MAPK molecules at transcriptional
                      (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was
                      observed in vitro. Additionally, we detected increased
                      expression and secretion of cytokines (CCL2, CX3CL1, CXCL10
                      and CCL7) upon MAPKi treatment, maintained during early
                      withdrawal. While increased cytokine expression did not have
                      tumor cell intrinsic effects, presence of these cytokines in
                      conditioned media led to increased attraction of microglia
                      cells in vitro.Taken together, these data indicate rapid
                      MAPK reactivation upon MAPKi withdrawal as a tumor cell
                      intrinsic rebound-driving mechanism. Furthermore, increased
                      secretion of microglia-recruiting cytokines may play a role
                      in treatment response and rebound growth upon withdrawal,
                      warranting further evaluation.},
      keywords     = {Cytokines (Other) / MAPK inhibitor (Other) / Pediatric
                      low-grade glioma (Other) / Rebound growth (Other) /
                      Treatment withdrawal (Other) / Tumor microenvironment
                      (Other)},
      cin          = {B310 / B300 / ED01 / B062 / B360 / FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)B300-20160331 /
                      I:(DE-He78)ED01-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)B360-20160331 / I:(DE-He78)FR01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38630384},
      doi          = {10.1007/s11060-024-04672-9},
      url          = {https://inrepo02.dkfz.de/record/289500},
}