Engineered cyclic peptide targeting ITGA5 disrupts tumor–stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma

TL;DR

A cyclic peptide targeting ITGA5 disrupts tumor-stroma interactions in pancreatic cancer, reducing resistance and improving chemotherapy effectiveness.

Contribution

A novel cyclic peptide (cyAV3.3) is developed to target ITGA5 and disrupt tumor-stroma interactions in pancreatic cancer.

Findings

cyAV3.3 inhibits pancreatic stellate cell differentiation into CAFs and reduces ECM production.

The peptide enhances gemcitabine efficacy by reducing resistance and stemness markers in 3D models.

In vivo, cyAV3.3 combined with gemcitabine improves therapeutic outcomes in PDAC models.

Abstract

The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin α5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. In vitro, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. In vivo, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG12D/+LSL-Trp53R172H/+Pdx1-Cre (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor–stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.

Engineered cyclic peptidomimetic inhibits activation of cancer-associated fibroblasts by targeting ITGA5/FAK axis, leading to reduced desmoplasia. This also inhibits tumor–stroma interaction, reducing stemness and resistance and increasing chemotherapy efficacy.Image 1

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