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

• Published in: Molecular therapy. Nucleic acids Vol. 32; pp. 111 - 126
• Main Authors: Ibba, Maria L., Ciccone, Giuseppe, Rotoli, Deborah, Coppola, Gabriele, Fiorelli, Alfonso, Catuogno, Silvia, Esposito, Carla L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-06-2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: aptamer; CAFs; chimeras; MT: Oligonucleotides: Therapies and Applications; NSCLC; Original; siRNA; STAT3; targeted delivery; chimeras; MT: Oligonucleotides: Therapies and Applications; NSCLC; CAFs; aptamer; STAT3; targeted delivery; siRNA
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2023.03.003

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.
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Cancer-associated fibroblasts (CAFs) are key mediators of tumor progression. This manuscript describes an innovative strategy to improve the treatment of non-small-cell lung cancer (NSCLC) patients that is a novel aptamer-based bio-drug inhibiting the interplay between cancer cells and CAFs.