TY - JOUR
T1 - ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer
AU - Kuninty, Praneeth R.
AU - Bansal, Ruchi
AU - De Geus, Susanna W.L.
AU - Mardhian, Deby F.
AU - Schnittert, Jonas
AU - van Baarlen, Joop
AU - Storm, Gert
AU - Bijlsma, Maarten F.
AU - van Laarhoven, Hanneke W.
AU - Metselaar, Josbert M.
AU - Kuppen, Peter J.K.
AU - Vahrmeijer, Alexander L.
AU - Östman, Arne
AU - Sier, Cornelis F.M.
AU - Prakash, Jai
PY - 2019/9/4
Y1 - 2019/9/4
N2 - Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.
AB - Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.
UR - http://www.scopus.com/inward/record.url?scp=85072123201&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aax2770
DO - 10.1126/sciadv.aax2770
M3 - Article
C2 - 31517053
AN - SCOPUS:85072123201
SN - 2375-2548
VL - 5
JO - Science advances
JF - Science advances
IS - 9
M1 - eaax2770
ER -