BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

Shin-Heng Chiou; Viviana I Risca; Gordon X Wang; Dian Yang; Barbara M Grüner; Arwa S Kathiria; Rosanna K Ma; Dedeepya Vaka; Pauline Chu; Margaret Kozak; Laura Castellini; Edward E Graves; Grace E Kim; Philippe Mourrain; Albert C Koong; Amato J Giaccia; Monte M Winslow

doi:10.1158/2159-8290.CD-17-0250

Back

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

Journal article

Open access

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

Shin-Heng Chiou, Viviana I Risca, Gordon X Wang, Dian Yang, Barbara M Grüner, Arwa S Kathiria, Rosanna K Ma, Dedeepya Vaka, Pauline Chu, Margaret Kozak, …

Cancer discovery, Vol.7(10), pp.1184-1199

10/2017

DOI: 10.1158/2159-8290.CD-17-0250

PMCID: PMC5628145

PMID: 28790031

Files and links (1)

url

https://doi.org/10.1158/2159-8290.CD-17-0250View

Published (Version of record) Open Access

Abstract

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. .

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

Details

Title: Subtitle: BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer
Creators: Shin-Heng Chiou - Stanford University
Viviana I Risca - Stanford University
Gordon X Wang - Stanford University
Dian Yang - Stanford University
Barbara M Grüner - Stanford University
Arwa S Kathiria - Stanford University
Rosanna K Ma - Stanford University
Dedeepya Vaka - Stanford University
Pauline Chu - Stanford University
Margaret Kozak - Stanford University
Laura Castellini - Stanford University
Edward E Graves - Stanford University
Grace E Kim - Department of Pathology, University of California, San Francisco, San Francisco, California
Philippe Mourrain - Stanford University
Albert C Koong - Stanford University
Amato J Giaccia - Stanford University
Monte M Winslow - Stanford University
Resource Type: Journal article
Publication Details: Cancer discovery, Vol.7(10), pp.1184-1199
DOI: 10.1158/2159-8290.CD-17-0250
PMID: 28790031
PMCID: PMC5628145
ISSN: 2159-8274
eISSN: 2159-8290
Grant note: R00 CA151968 / NCI NIH HHS P01 CA067166 / NCI NIH HHS R01 CA197136 / NCI NIH HHS R01 MH099647 / NIMH NIH HHS R01 CA198291 / NCI NIH HHS P30 CA124435 / NCI NIH HHS
Language: English
Date published: 10/2017
Academic Unit: Radiation Oncology
Record Identifier: 9984312967002771

Metrics

20 Record Views

52 Times Cited - Web of Science

See more details