Metastatic Competency and Tumor Spheroid Formation Are Independent Cell States Governed by RB in Lung Adenocarcinoma.
Metastatic Competency and Tumor Spheroid Formation Are Independent Cell States Governed by RB in Lung Adenocarcinoma.
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转移能力和肿瘤球体形成是由肺腺癌中RB控制的独立细胞态。
DOI：
10.1158/2767-9764.crc-23-0172
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发表时间：
2023-10-03
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影响因子：
--
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肺腺癌中视网膜母细胞瘤（RB）肿瘤抑制因子的失活与转移能力的快速获得和肺细胞谱系定型的丧失相关。我们以前的研究表明，小鼠晚期肺腺癌RB的恢复与肿瘤谱系消退和明显转移的频率降低相关。为了确定RB的因果关系及其在肺腺癌中重编程谱系定型和降低转移能力的作用，我们开发了多个肿瘤球体形成系，其中在表征每个球体的谱系定型和转移能力的程度后可以实现RB恢复。令人惊讶的是，我们发现RB失活显著促进了KrasLSL-G12 D/+; p53 flox/flox肺腺癌模型中出现的肿瘤中的肿瘤球体形成潜力。然而，RB重新激活没有影响的维持肿瘤球体线一旦建立。此外，我们表明，RB缺陷的肿瘤球体线是不均匀的转移能力，但同样可能是非转移性的。有趣的是，与肿瘤球体维持不同，RB恢复可以在功能上将转移性肿瘤球体恢复为非转移性细胞状态。因此，在肺癌中恢复RB通路活性的策略可能逆转转移能力并具有治疗潜力。最后，肿瘤球体形成潜力的获得反映了潜在的细胞状态可塑性，这通常是转移能力的预测，甚至与转移能力相混淆。我们的数据支持，每一个是一个离散的细胞状态限制RB和问题的适用性肿瘤球体模型的预测潜力，先进的转移性肿瘤细胞状态。RB通路的成员在肺腺癌中经常发生突变。我们发现RB调节细胞状态可塑性、肿瘤球体形成和转移能力。我们的数据表明，这些是独立的国家，球状体的形成是不同的转移能力。因此，我们警告不要混淆球状体形成和其他迹象的细胞状态可塑性与先进的转移性细胞状态。尽管如此，我们的工作支持临床策略，以重新激活RB途径。
Inactivation of the retinoblastoma (RB) tumor suppressor in lung adenocarcinoma is associated with the rapid acquisition of metastatic ability and the loss of lung cell lineage commitment. We previously showed that restoration of RB in advanced lung adenocarcinomas in the mouse was correlated with a decreased frequency of lineage decommitted tumors and overt metastases. To identify a causal relationship for RB and its role in reprogramming lineage commitment and reducing metastatic competency in lung adenocarcinoma, we developed multiple tumor spheroid forming lines where RB restoration could be achieved after characterization of the degree of each spheroid's lineage commitment and metastatic ability. Surprisingly, we discovered that RB inactivation dramatically promoted tumor spheroid forming potential in tumors that arise in the KrasLSL-G12D/+; p53flox/flox lung adenocarcinoma model. However, RB reactivation had no effect on the maintenance of tumor spheroid lines once established. In addition, we show that RB-deficient tumor spheroid lines are not uniformly metastatically competent but are equally likely to be nonmetastatic. Interestingly, unlike tumor spheroid maintenance, RB restoration could functionally revert metastatic tumor spheroids to a nonmetastatic cell state. Thus, strategies to reinstate RB pathway activity in lung cancer may reverse metastatic ability and have therapeutic potential. Finally, the acquisition of tumor spheroid forming potential reflects underlying cell state plasticity, which is often predictive of, or even conflated with metastatic ability. Our data support that each is a discrete cell state restricted by RB and question the suitability of tumor spheroid models for their predictive potential of advanced metastatic tumor cell states. Members of the RB pathway are frequently mutated in lung adenocarcinoma. We show that RB regulates cell state plasticity, tumor spheroid formation, and metastatic competency. Our data indicate that these are independent states where spheroid formation is distinct from metastatic competency. Thus, we caution against conflating spheroid formation and other signs of cell state plasticity with advanced metastatic cell states. Nevertheless, our work supports clinical strategies to reactivate RB pathways.
影响因子：
3.7
作者：
Kim KJ;Godarova A;Seedle K;Kim MH;Ince TA;Wells SI;Driscoll JJ;Godar S
通讯作者：
Godar S