DataSheet_2_Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSMRO.xlsx

Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients’ quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies. To overcome this challenge, we developed a new constraint-based computational method (COSMro) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for H2S production in radiation resistant cells and extracted a key relationship between intracellular redox state and cholesterol metabolism; experimental validation of this relationship highlights the importance of redox state in cellular metabolism and response to radiation.

氧化还原代谢（Redox metabolism）在癌症研究中愈发受到关注，其作为肿瘤进展、治疗应答及患者长期生活质量的关键调控因子。成熟的癌症治疗手段（如放射治疗（radiotherapy））既可直接作用于氧化还原代谢，也可通过氧化还原依赖的作用机制决定其临床疗效。然而，当前仍缺乏能够整合信号转导与代谢网络中的氧化还原信息，以助力癌症中氧化还原调控通路的发现与更广泛研究的能力，这一尚未满足的关键需求限制了新型癌症治疗手段的研发进展。为克服这一挑战，我们开发了一种新型基于约束的计算方法COSMro，并将其应用于头颈鳞状细胞癌（Head and Neck Squamous Cell Cancer, HNSCC）的放射抵抗模型。这一全新的整合分析方法在放射抵抗细胞中发现了硫化氢（H2S）产生能力的增强，并揭示了细胞内氧化还原状态与胆固醇代谢之间的关键关联；对该关联的实验验证凸显了氧化还原状态在细胞代谢及放射应答中的重要性。