Supplementary Table 2 from A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

Epithelial-mesenchymal transition (EMT) is an important axis of phenotypic plasticity – a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and, immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic ‘teams’ of players – while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell-states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network underlie the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.上皮间质转化（Epithelial-mesenchymal transition, EMT）是表型可塑性的重要调控轴，也是癌症转移的标志性特征。据报道，RAF激酶B抑制蛋白（Raf kinase-B inhibitor protein, RKIP）与BTB与CNC同源蛋白1（BTB and CNC homology 1, BACH1）均可调控EMT。二者在乳腺癌中呈拮抗作用，但其介导EMT及其他相关可塑性轴的确切作用机制仍不明确。本研究通过转录组数据分析，以泛癌视角揭示了二者与EMT、代谢重编程及经PD-L1介导的免疫逃逸相关的拮抗趋势。随后，本研究构建并模拟了一个基于机制的基因调控网络，该网络可阐释RKIP与BACH1如何与EMT及干性驱动因子形成反馈环路。研究发现，RKIP与BACH1分属两个相互拮抗的调控模块：BACH1所在的模块可促进促EMT、干细胞样及治疗耐药的细胞状态，而RKIP所在的模块则可维持促上皮、低干性及治疗敏感的细胞表型。最后，本研究观察到，在多种癌症类型中，RKIP低表达与BACH1高表达均与不良临床预后相关。综上，本研究的系统级分析表明，底层调控网络的涌现动力学，是RKIP与BACH1在癌症细胞可塑性各轴及患者生存数据中呈现拮抗模式的内在基础。