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000289500 245__ $$aRebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.
000289500 260__ $$aDordrecht [u.a.]$$bSpringer Science + Business Media B.V$$c2024
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000289500 500__ $$a#EA:B310#LA:B310# / 2024 Jun;168(2):317-332
000289500 520__ $$aPatients 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.
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000289500 650_7 $$2Other$$aCytokines
000289500 650_7 $$2Other$$aMAPK inhibitor
000289500 650_7 $$2Other$$aPediatric low-grade glioma
000289500 650_7 $$2Other$$aRebound growth
000289500 650_7 $$2Other$$aTreatment withdrawal
000289500 650_7 $$2Other$$aTumor microenvironment
000289500 7001_ $$aCao, Lei$$b1
000289500 7001_ $$aGuiho, Romain$$b2
000289500 7001_ $$aLanghammer, Melanie$$b3
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000289500 7001_ $$0P:(DE-He78)40aa4331020bebaf3e1801700d2d3267$$aValinciute, Gintvile$$b11
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000289500 7001_ $$aRemke, Marc$$b17
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000289500 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b20$$udkfz
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000289500 7001_ $$aMartinez-Barbera, Juan Pedro$$b25
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