Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization.
Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization.
复制标题
DOI：
10.1101/gad.263327.115
复制
发表时间：
2016-01-15
影响因子：
10.5
通讯作者：
Rustgi AK
中科院分区：
文献类型：
--
作者：
Takano S;Reichert M;Bakir B;Das KK;Nishida T;Miyazaki M;Heeg S;Collins MA;Marchand B;Hicks PD;Maitra A;Rustgi AK
Takano et al.描述配对相关同源结构域转录因子1(Prrx1)的两种异构体在转移级联中的新作用，使用互补的体外和体内模型。Prrx1b促进侵袭、肿瘤去分化和EMT。相反，Prrx1a刺激肝脏转移生长、肿瘤分化和MET。同源域转录因子1(Prrx1)的两个主要亚型Prrx1a和Prrx1b参与了胰腺发育、胰腺炎和肿瘤的发生，尽管这些亚型在胰腺导管腺癌(PDAC)全身扩散中的生物学作用尚未被研究。上皮-间充质转化(EMT)被认为是原发肿瘤进展和扩散的重要因素，而间充质-上皮转化(MET)似乎对转移性定植至关重要。在这里，我们使用互补的体外和体内模型描述了这两种异构体在转移级联中的新作用。Prrx1b促进侵袭、肿瘤去分化和EMT。相反，Prrx1a刺激肝脏转移生长、肿瘤分化和MET。我们进一步证明，从Prrx1b到Prrx1a的转换控制着PDAC小鼠模型和人类PDAC模型中的EMT可塑性。最后，我们确定肝细胞生长因子(HGF)是Prrx1b的一个新的转录靶点。在PDAC的临床前模型中，HGF联合吉西他滨的靶向治疗减少了原发肿瘤的体积，消除了转移疾病。总体而言，我们对Prrx1a和Prrx1b在原发PDAC的形成、扩散和转移定植中的异构体特异性作用提供了新的见解，从而允许针对EMT可塑性的新的治疗策略。
Takano et al. describe novel roles for both isoforms of paired-related homeodomain transcription factor 1 (Prrx1) in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial–mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal–epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.