Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes.

Abstract

BACKGROUND & AIMS:

Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice.

METHODS:

We used KRas(G12D) p53(R172H) Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes.

RESULTS:

Pancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRas(G12D) p53(R172H) Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial-mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence.

CONCLUSIONS:

The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer.

• Authors: Ang Li, Jennifer P Morton, YaFeng Ma, Saadia A Karim, Yan Zhou, William J Faller, Emma F Woodham, Hayley T Morris, Richard P Stevenson, Amelie Juin, Nigel B Jamieson, Colin J MacKay, C Ross Carter, Hing Y Leung, Shigeko Yamashiro, Karen Blyth, Owen J Sansom, Laura M Machesky
• Journal: Gastroenterology (Gastroenterology) Vol. 146 Issue 5 Pg. 1386-96.e1-17 (May 2014) ISSN: 1528-0012 [Electronic] United States
• PMID: 24462734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Microfilament Proteins
• SNAI1 protein, human
• Snai2 protein, mouse
• Snail Family Transcription Factors
• Transcription Factors
• fascin

Topics

• Animals
• Carcinoma in Situ (genetics, metabolism, pathology)
• Carcinoma, Pancreatic Ductal (genetics, metabolism, mortality, secondary)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Epithelial-Mesenchymal Transition
• Humans
• Mice
• Mice, Knockout
• Microfilament Proteins (deficiency, genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Pancreatic Neoplasms (genetics, metabolism, mortality, pathology)
• Prognosis
• Pseudopodia (metabolism)
• RNA Interference
• Snail Family Transcription Factors
• Survival Analysis
• Time Factors
• Transcription Factors (genetics, metabolism)
• Transfection