Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

Kuninty, P.; Bansal, R.; De Geus, S.; Schnittert, J.; van Baarlen, J.; Storm, G.; Bijlsma, M.; van Laarhoven, H.; Kuppen, P.; Vahrmeijer, A.; Ostman, A.; Sier, C.; Prakash, J.

doi:10.1101/350678

bioRxiv · 10.1101/350678

Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

Kuninty, P.·Bansal, R.·De Geus, S.·Schnittert, J.·van Baarlen, J.·Storm, G.·Bijlsma, M.·van Laarhoven, H.·Kuppen, P.·Vahrmeijer, A.·Ostman, A.·Sier, C.·Prakash, J.

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Abstract

Pancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-{beta}-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGF{beta}-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice. Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy.

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Kuninty, P., Bansal, R., De Geus, S., Schnittert, J., van Baarlen, J., Storm, G., Bijlsma, M., van Laarhoven, H., Kuppen, P., Vahrmeijer, A., Ostman, A., Sier, C., Prakash, J.. 2018-06-19. Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer. https://doi.org/10.1101/350678

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