TY - JOUR
T1 - Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5
AU - Young, Eric D.
AU - Manley, Sharon J.
AU - Beadnell, Thomas C.
AU - Shearin, Alexander E.
AU - Sasaki, Ken
AU - Zimmerman, Rosalyn
AU - Kauffman, Evan
AU - Vivian, Carolyn J.
AU - Parasuram, Aishwarya
AU - Iwakuma, Tomoo
AU - Grandgenett, Paul M.
AU - Hollingsworth, Michael A.
AU - O’Neil, Maura
AU - Welch, Danny R.
N1 - Funding Information:
Funding information The authors of this paper have research support from the NIH F30CA216998 (E.D.Y.), Kansas INBRE, P20 GM103418 (S.J.M. and D.R.W.), DOD BCRP BC171381 (T.C.B.), the University of Kansas Cancer Center Summer Student Research Training Program (A.E.S.), the Natl. Fndn. Cancer Res., CA168524, Hall Family Professorship in Molecular Medicine (D.R.W.), SPORE in Pancreatic Cancer, CA127297, TMEN Tumor Microenvironment Network, U54CA163120 and CA36727 (P.M.G. and M. A.H.).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2021/1/5
Y1 - 2021/1/5
N2 - Background: Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC. Methods: We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC. Results: Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases. Conclusions: Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
AB - Background: Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC. Methods: We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC. Results: Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases. Conclusions: Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
UR - http://www.scopus.com/inward/record.url?scp=85092101139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092101139&partnerID=8YFLogxK
U2 - 10.1038/s41416-020-01093-z
DO - 10.1038/s41416-020-01093-z
M3 - Article
C2 - 33024269
AN - SCOPUS:85092101139
VL - 124
SP - 166
EP - 175
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 1
ER -