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

Li, A. et al. (2014) Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. Gastroenterology, 146(5), 1386-1396.e17. (doi: 10.1053/j.gastro.2014.01.046) (PMID:24462734) (PMCID:PMC4000441)

Abstract

Background and 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 KRasG12D p53R172H 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 KRasG12D p53R172H 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carter, Mr Ross and Jamieson, Professor Nigel and Faller, Dr William and Li, Mr Ang and Ma, Dr Yafeng and Machesky, Professor Laura and Blyth, Professor Karen and Leung, Professor Hing and Morris, Dr Hayley and Zhou, Mr Yan and Stevenson, Dr Richard and Morton, Professor Jen and Juin, Dr Amelie and Karim, Ms Saadia and Sansom, Professor Owen
• Authors: Li, A., Morton, J. P., Ma, Y., Karim, S. A., Zhou, Y., Faller, W. J., Woodham, E. F., Morris, H. T., Stevenson, R. P., Juin, A., Jamieson, N. B., MacKay, C. J., Carter, C. R., Leung, H. Y., Yamashiro, S., Blyth, K., Sansom, O. J., and Machesky, L. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Gastroenterology
• Publisher: WB Saunders
• ISSN: 0016-5085
• ISSN (Online): 1528-0012|
• Copyright Holders: Copyright © 2014 AGA Institute
• First Published: First published in Gastroenterology 146(5):1386-1396.e17
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher