Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, 200433, China.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2404854. doi: 10.1002/advs.202404854. Epub 2024 Sep 11.
Cancer is a systemic heterogeneous disease involving complex molecular networks. Tumor formation involves an epithelial-mesenchymal transition (EMT), which promotes both metastasis and plasticity of cancer cells. Recent experiments have proposed that cancer cells can be transformed into adipocytes via a combination of drugs. However, the underlying mechanisms for how these drugs work, from a molecular network perspective, remain elusive. To reveal the mechanism of cancer-adipose conversion (CAC), this study adopts a systems biology approach by combing mathematical modeling and molecular experiments, based on underlying molecular regulatory networks. Four types of attractors are identified, corresponding to epithelial (E), mesenchymal (M), adipose (A) and partial/intermediate EMT (P) cell states on the CAC landscape. Landscape and transition path results illustrate that intermediate states play critical roles in the cancer to adipose transition. Through a landscape control approach, two new therapeutic strategies for drug combinations are identified, that promote CAC. These predictions are verified by molecular experiments in different cell lines. The combined computational and experimental approach provides a powerful tool to explore molecular mechanisms for cell fate transitions in cancer networks. The results reveal underlying mechanisms of intermediate cell states that govern the CAC, and identified new potential drug combinations to induce cancer adipogenesis.
癌症是一种涉及复杂分子网络的系统性异质疾病。肿瘤的形成涉及上皮-间充质转化（EMT），它促进了癌细胞的转移和可塑性。最近的实验提出，癌细胞可以通过药物组合转化为脂肪细胞。然而，从分子网络的角度来看，这些药物如何发挥作用的潜在机制仍不清楚。为了揭示癌症向脂肪转化（CAC）的机制，本研究采用系统生物学方法，结合数学建模和分子实验，基于潜在的分子调控网络。在 CAC 景观上，确定了四种吸引子，分别对应上皮（E）、间充质（M）、脂肪（A）和部分/中间 EMT（P）细胞状态。景观和过渡路径结果表明，中间状态在癌症向脂肪的转化中起着关键作用。通过景观控制方法，确定了两种促进 CAC 的新药物组合治疗策略。这些预测通过不同细胞系的分子实验得到了验证。这种组合的计算和实验方法为探索癌症网络中细胞命运转变的分子机制提供了有力的工具。研究结果揭示了中间细胞状态控制 CAC 的潜在机制，并确定了新的潜在药物组合来诱导癌症脂肪生成。
