Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations.
Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations.
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DOI：
10.1038/s41598-023-46055-6
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发表时间：
2023-11-06
影响因子：
4.6
通讯作者：
Dawson, Michelle R.
中科院分区：
文献类型：
--
作者：
Pena, Carolina Mejia;Skipper, Thomas A.;Hsu, Jeffrey;Schechter, Ilexa;Ghosh, Deepraj;Dawson, Michelle R.
超过75%的上皮性卵巢癌(EOC)患者在最初治疗后经历疾病复发，这突显了我们对化疗后耐药人群如何在EOC进展过程中演变的不完全了解。在这里，我们展示了两种紫杉醇(PTX)治疗方法--单次大剂量和每周节律剂量，为期四周，如何产生独特的化疗耐药人群。使用机械相关的藻酸盐微球以及转录图谱和异质性分析相结合的方法，我们发现这些PTX治疗方案产生了不同的、具有弹性的亚群，这些亚群在代谢重编程特征、对PTX和失巢凋亡的抗性获得以及肿瘤干细胞(CSCs)和具有补充大量种群的能力的多倍体巨型癌细胞(PGCCs)的富集性方面存在差异。我们使用非靶向代谢组学研究了这些代谢重编程事件的寿命，发现与干性和治疗诱导的衰老相关的代谢物在CSCs和PGCCs丰富的种群中独一无二地丰富。预测网络分析显示，抗氧化机制可能是不同的活性取决于时间和接触PTX。我们的结果说明了当前的标准化疗是如何通过选择内在耐药的亚群或促进耐药机制的进化来促进耐药的EoC亚群的发展。此外，我们的工作描述了每个不同抗性亚群中的独特表型特征，从而突出了可用于更有效治疗的潜在脆弱性。
More than 75% of epithelial ovarian cancer (EOC) patients experience disease recurrence after initial treatment, highlighting our incomplete understanding of how chemoresistant populations evolve over the course of EOC progression post chemotherapy treatment. Here, we show how two paclitaxel (PTX) treatment methods- a single high dose and a weekly metronomic dose for four weeks, generate unique chemoresistant populations. Using mechanically relevant alginate microspheres and a combination of transcript profiling and heterogeneity analyses, we found that these PTX-treatment regimens produce distinct and resilient subpopulations that differ in metabolic reprogramming signatures, acquisition of resistance to PTX and anoikis, and the enrichment for cancer stem cells (CSCs) and polyploid giant cancer cells (PGCCs) with the ability to replenish bulk populations. We investigated the longevity of these metabolic reprogramming events using untargeted metabolomics and found that metabolites associated with stemness and therapy-induced senescence were uniquely abundant in populations enriched for CSCs and PGCCs. Predictive network analysis revealed that antioxidative mechanisms were likely to be differentially active dependent on both time and exposure to PTX. Our results illustrate how current standard chemotherapies contribute to the development of chemoresistant EOC subpopulations by either selecting for intrinsically resistant subpopulations or promoting the evolution of resistance mechanisms. Additionally, our work describes the unique phenotypic signatures in each of these distinct resistant subpopulations and thus highlights potential vulnerabilities that can be exploited for more effective treatment.
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影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
影响因子：
3.8
作者：
Jablonska E;Gromadzinska J;Peplonska B;Fendler W;Reszka E;Krol MB;Wieczorek E;Bukowska A;Gresner P;Galicki M;Zambrano Quispe O;Morawiec Z;Wasowicz W
通讯作者：
Wasowicz W
影响因子：
2.1
作者：
Flesken-Nikitin A;Odai-Afotey AA;Nikitin AY
通讯作者：
Nikitin AY
影响因子：
5.2
作者：
Lee AH;Mejia Peña C;Dawson MR
通讯作者：
Dawson MR
影响因子：
3.7
作者：
Anderson AS;Roberts PC;Frisard MI;Hulver MW;Schmelz EM
通讯作者：
Schmelz EM