JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States.
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States.
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DOI：
10.1158/0008-5472.can-22-0423
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发表时间：
2023-01-18
期刊：
影响因子：
11.2
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中科院分区：
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炎性乳腺癌（IBC）是一种难以治疗的疾病，由于转移风险高和治疗耐药，临床结果不佳。在乳腺癌中，CD44+CD24−细胞具有干细胞样特征并有助于疾病进展，我们之前描述了依赖于JAK2/STAT3信号传导的CD44+CD24−pSTAT3+乳腺癌细胞亚群。在这里，我们报告 CD44+CD24− 细胞是 IBC 中最常见的细胞类型，通常为 pSTAT3+。 JAK2/STAT3 抑制与紫杉醇的组合比单独使用任一药物更能减少 IBC 异种移植物的生长。对紫杉醇和阿霉素具有耐药性的 IBC 细胞系被开发出来并进行表征，以模拟患者的治疗耐药性。亲代细胞和耐药细胞的多组学分析揭示了与化疗耐药衍生物中的谱系特性和炎症相关的基因的富集。整合的 pSTAT3 ChIP-seq 和 RNA-seq 分析显示，pSTAT3 调节耐药细胞中与炎症和上皮间质转化 (EMT) 相关的基因，以及 PDE4A（一种 cAMP 特异性磷酸二酯酶）。代谢组学特征确定 cAMP 信号传导升高和 CREB 作为 IBC 的候选治疗靶点。通过 CyTOF 和单细胞 RNA-seq 对化疗期间单细胞水平的细胞动力学和异质性进行研究，并通过 CyTOF 和单细胞 RNA-seq 确定了耐药机制，包括通过选择稀有的预先存在的亚群或获得性变化，从腔细胞状态转变为基底/间充质细胞状态。最后，紫杉醇和 JAK2/STAT3 抑制的联合治疗阻止了间充质化疗耐药亚群的出现。这些结果为联合化疗与抑制 JAK2/STAT3 信号传导作为 IBC 更有效的治疗策略提供了机制合理性。
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24− cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24−pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24− cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.