BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human...

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Bibliographic Details
Published in:Cancer discovery 2017-10, Vol.7 (10), p.1184-1199
Main Authors: Chiou, Shin-Heng, Risca, Viviana I, Wang, Gordon X, Yang, Dian, Grüner, Barbara M, Kathiria, Arwa S, Ma, Rosanna K, Vaka, Dedeepya, Chu, Pauline, Kozak, Margaret, Castellini, Laura, Graves, Edward E, Kim, Grace E, Mourrain, Philippe, Koong, Albert C, Giaccia, Amato J, Winslow, Monte M
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Hypoxia
Cell Line, Tumor
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Genetic Engineering
Humans
Mice
Neoplasm Metastasis
Neoplasm Transplantation
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Positive Regulatory Domain I-Binding Factor 1 - genetics
Sequence Analysis, RNA - methods
Tumor Microenvironment
Up-Regulation
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-17-0250