Bukkuri Anuraag, Andersson Stina, Mazariegos Marina S, Brown Joel S, Hammarlund Emma U, Mohlin Sofie
University of Pittsburgh School of Medicine, Department of Computational and Systems Biology, Pittsburgh, PA, USA.
The Center for Philosophy of Science at the University of Pittsburgh, Pittsburgh, PA, USA.
iScience. 2024 Nov 19;27(12):111433. doi: 10.1016/j.isci.2024.111433. eCollection 2024 Dec 20.
Neuroblastoma exhibits two cellular phenotypes: therapy-sensitive adrenergic (ADRN) and therapy-resistant mesenchymal (MES). To understand treatment response, it is important to elucidate how these phenotypes impact the dynamics of cancer cell populations and whether they represent distinct cell types or dynamic cell states. Here, we use an integrated experimental and mathematical modeling approach. We experimentally measure the fractions of ADRN and MES phenotypes under baseline (untreated) conditions and under repeated treatment cycles. We develop evolutionary game theoretic models predicting how the populations would respond if ADRN and MES phenotypes (1) are distinct cell types or (2) represent dynamic cell states and fit these models to the experimental data. We find that, although cells may undergo an ADRN to MES phenotypic switch under treatment, the best-fit model sees ADRN and MES as distinct cell types. Differential proliferation and survival of these two cell types, and not cell-state switching, drive therapeutic response.
对治疗敏感的肾上腺素能型（ADRN）和对治疗耐药的间充质型（MES）。为了解治疗反应，阐明这些表型如何影响癌细胞群体的动态变化以及它们代表的是不同的细胞类型还是动态的细胞状态非常重要。在此，我们采用综合实验和数学建模方法。我们通过实验测量在基线（未治疗）条件下以及重复治疗周期下ADRN和MES表型的比例。我们开发了进化博弈论模型，预测如果ADRN和MES表型（1）是不同的细胞类型或（2）代表动态细胞状态，群体将如何反应，并将这些模型与实验数据进行拟合。我们发现，尽管细胞在治疗过程中可能会发生从ADRN到MES的表型转换，但最佳拟合模型将ADRN和MES视为不同的细胞类型。这两种细胞类型的增殖和存活差异，而非细胞状态转换，驱动了治疗反应。
