Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
Gastroenterology. 2021 Jul;161(1):318-332.e9. doi: 10.1053/j.gastro.2021.03.051. Epub 2021 Apr 2.
BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.
Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes.
Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.
We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.
不同亚型的胰腺导管腺癌（PDAC）的存在及其与患者预后的相关性，已经将患者分类的重点转移到更好的决策算法和个性化治疗上。调节癌症干细胞（CSC）群体的机制在不同亚型中的作用尚不清楚。
使用 RNA-seq，我们确定了 B 细胞 CLL/淋巴瘤 3（BCL3），一种非典型的 NF-κB 信号成员，在胰腺 CSCs 中存在差异。为了确定 BCL3 沉默在体内和体外的生物学后果，我们生成了 bcl3 缺陷的临床前小鼠模型以及鼠细胞系，并将我们的发现与人类细胞系、PDX 模型和 2 个独立的患者队列相关联。我们评估了 bcl3 表达模式与临床参数和亚型的相关性。
BCL3 在人类 CSCs 中显著下调。通过 BCL3 基因敲除在 PDAC 的临床前小鼠模型中重现这种表型，增强了肿瘤负担、转移、上皮间质转化和总体生存的减少。荧光激活细胞分选分析，以及耗氧量、球体形成和肿瘤发生测定，都表明 BCL3 缺失导致 CSC 区室扩张，促进细胞去分化。BCL3 在人 PDX 中的过表达通过显著减少 CSC 群体和促进分化来抑制肿瘤生长。BCL3 低表达的人 PDAC 与转移增加相关，而 BCL3 阴性肿瘤与存活率降低和非经典亚型相关。
我们证明，bcl3 通过抑制 CSC 扩张和减少 PDAC 中侵袭性和转移性肿瘤负担，对胰腺发生有影响。BCL3 表达水平是预测 PDAC 亚型特征的有用分层标志物，从而允许进行个性化的治疗方法。
