TY - JOUR
T1 - Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization
AU - Takano, Shigetsugu
AU - Reichert, Maximilian
AU - Bakir, Basil
AU - Das, Koushik K.
AU - Nishida, Takahiro
AU - Miyazaki, Masaru
AU - Heeg, Steffen
AU - Collins, Meredith A.
AU - Marchand, Benoît
AU - Hicks, Philip D.
AU - Maitra, Anirban
AU - Rustgi, Anil K.
N1 - Publisher Copyright:
© 2016 Takano et al.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - 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 iso-forms 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 dis-semination, 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.
AB - 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 iso-forms 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 dis-semination, 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.
KW - EMT
KW - MET
KW - Metastasis
KW - Pancreatic cancer
KW - Prrx1a
KW - Prrx1b
UR - http://www.scopus.com/inward/record.url?scp=84954480754&partnerID=8YFLogxK
U2 - 10.1101/gad.263327.115
DO - 10.1101/gad.263327.115
M3 - Article
C2 - 26773005
AN - SCOPUS:84954480754
SN - 0890-9369
VL - 30
SP - 233
EP - 247
JO - Genes and Development
JF - Genes and Development
IS - 2
ER -