title: FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells.
abstract: Biological heterogeneity represents a major obstacle for cancer treatment. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more effective therapies in the future. Here, we uncovered population heterogeneity among PAX/FOXO1-positive alveolar rhabdomyosarcoma by characterizing prosurvival networks initiated by FGFR4 signaling. We found that FGFR4 signaling rescues only subgroups of alveolar rhabdomyosarcoma cells from apoptosis induced by compounds targeting the IGF1R-PI3K-mTOR pathway. Differences in both proapoptotic machinery and FGFR4-activated signaling are involved in the different behavior of the phenotypes. Proapoptotic stress induced by the kinase inhibitors is sensed by Bim/Bad in rescue cells and by Bmf in nonrescue cells. Anti-apoptotic ERK1/2 signaling downstream of FGFR4 is long-lasting in rescue and short-termed in most non-rescue cells. Gene expression analysis detected signatures specific for these two groups also in biopsy samples. The different cell phenotypes are present in different ratios in alveolar rhabdomyosarcoma tumors and can be identified by AP2β expression levels. Hence, inhibiting FGFR signaling might represent an important strategy to enhance efficacy of current RMS treatments.
authors.affiliation: Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, Zurich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Wachtel
authors.forename: Jelena
authors.initials: J
authors.lastname: Rakic
authors.forename: Michal
authors.initials: M
authors.lastname: Okoniewski
authors.forename: Peter
authors.initials: P
authors.lastname: Bode
authors.forename: Felix
authors.initials: F
authors.lastname: Niggli
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018232:Rhabdomyosarcoma, Alveolar / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C546842:MTOR protein, human; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases
keywords: BH3-only proteins; FGFR4; alveolar rhabdomyosarcoma; tumor heterogeneity