Tumor-penetrating therapy for \u03b25 integrin-rich pancreas cancer

Tatiana Hurtado De Mendoza,Venkata R Kotamraju,Kazuki N Sugahara,Gregory P Botta,Randall P French,Erkki Ruoslahti,Kodai Suzuki,Tambet Teesalu,Norio Miyamura,Evangeline S Mose,Gary B Braun,Andrew M Lowy

doi:10.1038/s41467-021-21858-1

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue
Fluorescein (FAM)-labeled iRGD rapidly distributed throughout the tumor stroma within the first 15 min, and gradually spread into adjacent tumor cells in the 15 min (Fig. 1a, upper panels). iRGD entered early pancreatic intraepithelial neoplasia (PanINs) after infiltrating the surrounding desmoplasia (Fig. 1a, lower panels)
First recognized as an angiogenic integrin, β5 integrin in the form of αvβ[5] has been viewed as a tumor-specific signature that selectively directs iRGD to tumor blood vessels as the initial step of tumor-specific tissue penetration19. iRGD enriched at tumor blood vessels is proteolytically processed into CRGDK, which leads to increased affinity to NRP-119

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. We report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumorpenetrating peptide iRGD. TGF-β secreted by CAFs provides autocrine signals to sustain the collagen-producing myofibroblast phenotype, and affects cancer cells in a paracrine fashion to increase their adhesion, proliferation, migration, and invasion by regulating gene expression[7,10]. During tumor development and progression, the αvβ[5] integrin governs critical events, such as angiogenesis, by activating the focal adhesion kinase–steroid receptor coactivator pathway[16]. This activity is complemented by the αvβ[3] integrin, which regulates the p21activated kinase pathway[16]. Injected iRGD targets αvβ[3] and αvβ[5] integrins selectively expressed on angiogenic tumor blood vessels via its RGD motif

Methods

Results

Conclusion