Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization

Shigetsugu Takano, Maximilian Reichert, Basil Bakir, Koushik K. Das, Takahiro Nishida, Masaru Miyazaki, Steffen Heeg, Meredith A. Collins, Benoît Marchand, Philip D. Hicks, Anirban Maitra, Anil K. Rustgi

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)233-247
Number of pages15
JournalGenes and Development
Volume30
Issue number2
DOIs
StatePublished - Jan 15 2016
Externally publishedYes

Keywords

  • EMT
  • MET
  • Metastasis
  • Pancreatic cancer
  • Prrx1a
  • Prrx1b

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  • Cite this

    Takano, S., Reichert, M., Bakir, B., Das, K. K., Nishida, T., Miyazaki, M., Heeg, S., Collins, M. A., Marchand, B., Hicks, P. D., Maitra, A., & Rustgi, A. K. (2016). Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes and Development, 30(2), 233-247. https://doi.org/10.1101/gad.263327.115