癌相关成纤维细胞（CAFs）是肿瘤微环境（TME）中的关键参与者，与癌症的发生、发展和对治疗的抵抗密切相关。它们表现出具有侵袭性的表型，影响细胞外基质重塑、血管生成、免疫系统调节、肿瘤生长和增殖。CAF的表型变化似乎与代谢改变有关，特别是逆沃尔伯格效应，可能推动成纤维细胞的转化。然而，其精确的分子机制和调控驱动因子仍在研究中。解析乳腺癌CAF中的逆沃尔伯格效应可能有助于更好地理解TME与肿瘤细胞之间的相互作用，从而引发新的治疗策略。在这方面，能够跨越多个生物层次的动态建模方法对于捕捉复杂且纠缠的途径涉及的多个生物实体的新兴特性至关重要。本工作提出了首个涵盖主要细胞信号传导、基因调控和代谢过程的大规模混合计算模型，用于乳腺CAF。该模型通过将细胞和疾病特异性的异步布尔模型与通用核心代谢网络相结合，利用数据驱动和手动修正的方法生成。该模型能够复制在乳腺CAF中实验观察到的逆沃尔伯格效应，并进一步确定缺氧诱导因子1（HIF-1）作为其关键分子驱动因子。将HIF-1作为以TME为中心的治疗策略的一部分进行靶向可能有助于治疗乳腺癌，解决逆沃尔伯格效应。鉴于我们先前发表的类风湿关节炎滑膜成纤维细胞的结果，CAF中的这些发现提示乳腺癌和类风湿关节炎中都存在由HIF-1驱动的代谢重编程的共同点。©2023作者们。

Cancer-associated fibroblasts (CAFs) are amongst the key players of the tumor microenvironment (TME) and are involved in cancer initiation, progression, and resistance to therapy. They exhibit aggressive phenotypes affecting extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining a cell- and disease-specific asynchronous Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, in light of our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.© 2023 The Authors.