Mu Peiyuan, Mo Shaobo, He Xingfeng, Zhang Hui, Lv Tao, Xu Ruone, He Luoxi, Xia Fan, Zhou Shujuan, Chen Yajie, Wang Yaqi, Shen Lijun, Wan Juefeng, Huang Lili, Lu Weiqing, Liang Xinyue, Li Xiaomeng, Lu Ping, Peng Junjie, Hua Guoqiang, Hu Kewen, Zhang Zhen, Wang Yan
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
J Exp Clin Cancer Res. 2025 Mar 11;44(1):92. doi: 10.1186/s13046-025-03349-z.
Radiotherapy (RT) is an essential treatment for colorectal cancer (CRC), yet the factors influencing radiosensitivity remain unclear. In the quest to enhance the therapeutic efficacy in CRC, the interplay between genetic mutations and RT sensitivity has emerged as a pivotal yet enigmatic area.
We harness the fidelity of patient-derived organoids (PDOs) to dissect the molecular landscape of radiosensitivity, with a particular emphasis on BRAF mutations. To further investigate, a cohort of 9 BRAF-mutant and 10 BRAF wild-type PDOs is constructed to systematically assess the radiobiological traits of BRAF-mutant CRC, including morphology, cell viability, and DNA damage, while also evaluating their responses to chemotherapy and chemoradiotherapy.
Our systematic investigation unveils a profound correlation between BRAF mutation status and radioresistance, which is validated by clinical treatment responses. Intriguingly, BRAF-mutant PDOs exhibit reduced sensitivity to conventional chemotherapy, yet demonstrate an enhanced response to combined chemoradiotherapy, characterized by increased apoptosis. The results are validated through in vivo analyses using patient-derived organoid xenograft mouse models and aligned with patient clinical outcomes.
This study outlines the distinct radiobiological profile of BRAF-mutant CRC, underscoring the critical role of radiotherapy in comprehensive treatment strategies. This work not only advances our molecular understanding of CRC but also paves the way for precision medicine, offering valuable insights for therapeutic decision-making in the clinical management of BRAF-mutant CRC.
放射治疗（RT）是结直肠癌（CRC）的重要治疗方法，但影响放射敏感性的因素仍不清楚。在寻求提高CRC治疗效果的过程中，基因突变与放射敏感性之间的相互作用已成为一个关键但神秘的领域。
我们利用患者来源的类器官（PDO）的保真度来剖析放射敏感性的分子格局，特别关注BRAF突变。为了进一步研究，构建了一组9个BRAF突变型和10个BRAF野生型PDO，以系统评估BRAF突变型CRC的放射生物学特征，包括形态、细胞活力和DNA损伤，同时评估它们对化疗和放化疗的反应。
我们的系统研究揭示了BRAF突变状态与放射抗性之间的深刻相关性，这在临床治疗反应中得到了验证。有趣的是，BRAF突变型PDO对传统化疗的敏感性降低，但对联合放化疗表现出增强的反应，其特征是细胞凋亡增加。结果通过使用患者来源的类器官异种移植小鼠模型的体内分析得到验证，并与患者的临床结果一致。
本研究概述了BRAF突变型CRC独特的放射生物学特征，强调了放射治疗在综合治疗策略中的关键作用。这项工作不仅推进了我们对CRC的分子理解，也为精准医学铺平了道路，为BRAF突变型CRC临床管理中的治疗决策提供了有价值的见解。
