Cellular plasticity is the ability of cells to alter their identity and acquire new biological properties. In the context of cancer, plasticity may explain how certain tumors evolve and become resistant to therapy. Chan et al. investigated the molecular mechanisms underlying lineage plasticity in late-stage prostate cancer. Using a number of model systems, including human organoid cultures, activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) and fibroblast growth factor receptor (FGFR) signaling was found to drive prostate tumor plasticity. Pharmacological targeting of the JAK and FGFR pathways promoted lineage reprogramming in biopsy samples from castration-resistant prostate cancer patients. These findings provide insights that may help to curb prostate cancer progression and resensitize resistant tumors to effective therapies. —PNK
Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.
细胞可塑性是指细胞改变其身份并获得新生物学特性的能力。在癌症背景下，可塑性可能解释了某些肿瘤如何演变并对治疗产生抵抗。Chan等人研究了晚期前列腺癌中谱系可塑性的分子机制。通过使用多种模型系统，包括人类类器官培养，研究发现Janus激酶-信号转导和转录激活因子（JAK/STAT）以及成纤维细胞生长因子受体（FGFR）信号通路的激活会驱动前列腺肿瘤的可塑性。对JAK和FGFR通路的药物靶向促进了去势抵抗性前列腺癌患者活检样本中的谱系重编程。这些发现提供了可能有助于遏制前列腺癌进展并使耐药肿瘤重新对有效疗法敏感的见解。—PNK
癌症中的耐药性通常与肿瘤细胞状态或谱系的变化有关，但驱动这种可塑性的分子机制仍不清楚。我们利用小鼠类器官和基因工程小鼠模型，研究了前列腺癌中谱系可塑性的原因及其与抗雄激素耐药性的关系。我们发现可塑性起始于一种由混合腔-基底表型定义的上皮细胞群，并且它依赖于Janus激酶（JAK）和成纤维细胞生长因子受体（FGFR）活性的增强。来自携带混合谱系细胞的去势抵抗性疾病患者的类器官培养，通过JAK和FGFR抑制剂处理后上调腔细胞基因表达，重现了在小鼠中观察到的依赖性。单细胞分析证实，在一部分转移性疾病患者中存在具有增强的JAK/STAT（信号转导和转录激活因子）和FGFR信号传导的混合谱系细胞，这对临床试验中患者的分类具有参考意义。
Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling
肿瘤(癌症)患者之家