STAT3 silencing by an aptamer-based strategy hampers the crosstalk between NSCLC cells and cancer-associated fibroblasts

Maria L Ibba; Giuseppe Ciccone; Deborah Rotoli; Gabriele Coppola; Alfonso Fiorelli; Silvia Catuogno; Carla L Esposito

doi:10.1016/j.omtn.2023.03.003

STAT3 silencing by an aptamer-based strategy hampers the crosstalk between NSCLC cells and cancer-associated fibroblasts

Mol Ther Nucleic Acids. 2023 Mar 10:32:111-126. doi: 10.1016/j.omtn.2023.03.003. eCollection 2023 Jun 13.

Authors

Maria L Ibba^{1

2}, Giuseppe Ciccone¹, Deborah Rotoli¹, Gabriele Coppola^{1

3}, Alfonso Fiorelli⁴, Silvia Catuogno¹, Carla L Esposito¹

Affiliations

¹ Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy.
² Department of Precision Medicine, University of Campania "L. Vanvitelli", 80138 Naples, Italy.
³ Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, 80131 Naples, Italy.
⁴ Thoracic Surgery Unit, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Abstract

The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.

Keywords: CAFs; MT: Oligonucleotides: Therapies and Applications; NSCLC; STAT3; aptamer; chimeras; siRNA; targeted delivery.