Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, Zurich, Switzerland.
Int J Cancer. 2014 Oct 1;135(7):1543-52. doi: 10.1002/ijc.28800. Epub 2014 Mar 3.
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.
生物异质性是癌症治疗的主要障碍。因此，为了未来开发更有效的治疗方法，有必要对与治疗相关的肿瘤异质性进行特征描述。在这里，我们通过对 FGFR4 信号引发的生存相关网络进行特征描述，揭示了 PAX/FOXO1 阳性肺泡横纹肌肉瘤中的群体异质性。我们发现，FGFR4 信号仅能挽救靶向 IGF1R-PI3K-mTOR 通路的化合物诱导的凋亡的肺泡横纹肌肉瘤细胞亚群。促凋亡机制和 FGFR4 激活的信号通路的差异参与了表型的不同行为。在挽救细胞中，促凋亡应激由 Bim/Bad 感知，而在非挽救细胞中由 Bmf 感知。FGFR4 下游的抗凋亡 ERK1/2 信号在挽救细胞中持续时间较长，而在大多数非挽救细胞中持续时间较短。基因表达分析在活检样本中也检测到了这两个群体的特异性特征。在肺泡横纹肌肉瘤肿瘤中，不同的细胞表型以不同的比例存在，并可以通过 AP2β 表达水平来识别。因此，抑制 FGFR 信号可能代表增强当前 RMS 治疗效果的重要策略。
