Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes.
OBJECTIVE
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.
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Ang
A
Li
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Jennifer P
JP
Morton
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
YaFeng
Y
Ma
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Saadia A
SA
Karim
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Yan
Y
Zhou
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
William J
WJ
Faller
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Emma F
EF
Woodham
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Hayley T
HT
Morris
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Richard P
RP
Stevenson
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Amelie
A
Juin
Department of Surgery, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
Nigel B
NB
Jamieson
Department of Surgery, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
Colin J
CJ
MacKay
Department of Surgery, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
C Ross
CR
Carter
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Hing Y
HY
Leung
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
Shigeko
S
Yamashiro
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Karen
K
Blyth
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Owen J
OJ
Sansom
CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Electronic address: l.machesky@beatson.gla.ac.uk.
Laura M
LM
Machesky
D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D002352:Carrier Proteins; D008840:Microfilament Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C020324:fascin
Actin Cytoskeleton; EMT; Pancreas; Tumor Progression