ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

Praneeth R. Kuninty, Ruchi Bansal, Susanna W. L. de Geus, Deby F. Mardhian, Jonas Schnittert, Joop van Baarlen, Gert Storm, Maarten F. Bijlsma, Hanneke W. van Laarhoven, Josbert M. Metselaar, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Arne Östman, Cornelis F. M. Sier, Jai Prakash

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article numbereaax2770
JournalScience Advances
Volume5
Issue number9
DOIs
Publication statusPublished - 4 Sep 2019
Externally publishedYes

Cite this

Kuninty, P. R., Bansal, R., de Geus, S. W. L., Mardhian, D. F., Schnittert, J., van Baarlen, J., ... Prakash, J. (2019). ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Science Advances, 5(9), [eaax2770]. https://doi.org/10.1126/sciadv.aax2770