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Chimeric TβRII-SE/Fc overexpression by a lentiviral vector exerts strong antitumoral activity on colorectal cancer-derived cell lines in vitro and on xenografts

Cancer Gene Therapy volume 31, pages 174–185 (2024)Cite this article

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Abstract

The TGF signaling pathway is a key regulator of cancer progression. In this work, we report for the first time the antitumor activity of TβRII-SE/Fc, a novel peptibody whose targeting domain is comprised of the soluble endogenous isoform of the human TGF-β type II receptor (TβRII-SE). Overexpression of TβRIISE/Fc reduces in vitro cell proliferation and migration while inducing cell cycle arrest and apoptosis in human colorectal cancer-derived cell lines. Moreover, TβRII-SE/Fc overexpression reduces tumorigenicity in BALB/c nude athymic mice. Our results revealed that TRII-SE/Fc-expressing tumors were significantly reduced in size or were even incapable of developing. We also demonstrated that the novel peptibody has the ability to inhibit the canonical TGF-β and BMP signaling pathways while identifying SMAD-dependent and independent proteins involved in tumor progression that are modulated by TβRII-SE/Fc. These findings provide insights into the underlying mechanism responsible for the antitumor activity of TβRII-SE/Fc. Although more studies are required to demonstrate the effectiveness and safety of the novel peptibody as a new therapeutic for the treatment of cancer, our initial in vitro and in vivo results in human colorectal tumor-derived cell lines are highly encouraging. Our results may serve as the foundation for further research and development of a novel biopharmaceutical for oncology.

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Fig. 1: TβRII-SE/Fc inhibits the cell cycle and induces apoptosis.
Fig. 2: Overexpression of TβRII-SE/Fc decreases cell proliferation and migration of human colorectal cancer-derived cell lines HCT116 and HT29.
Fig. 3: Overexpression of TβRII-SE/Fc reduces the tumorigenicity of human colorectal cancer-derived cells in xenograft models.
Fig. 4: TβRII-SE/Fc reduces cell proliferation and increases apoptosis in vivo.
Fig. 5: Molecular changes induced by TβRII-SE/Fc overexpression in HCT116 and HT29 cell-derived tumors.

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The datasets generated or analysed during the current study are available from the corresponding authors on request.

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Acknowledgements

We thank Prof. Dr. Li Baojie from the Bio-X Institutes, Shanghai Jiao Tong University for the facilities and reagents provided for this project.

Funding

This work was supported, in part, by the National Scientific and Technical Research Council of Argentina (CONICET) research grants PIP 2013 GI, 11220120100202CO, and PIP 2017 GI, 11220170100573CO, and PICT-2020-SERIE A-03635, from Agencia I + D + i de Argentina, as well as funding from Fundación Florencio Fiorini (Academia Nacional de Medicina, Buenos Aires, Argentina).

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Authors and Affiliations

  1. Laboratorio de Terapia Génica y Células Madre, Instituto Tecnológico de Chascomús (INTECH), CONICET-UNSAM), Chascomús, Argentina

    Ana Romo, Tania Melina Rodríguez & Ricardo Alfredo Dewey

  2. Escuela de Bio y Nanotecnologías, Universidad Nacional de San Martín (UNSAM), Buenos Aires, Argentina

    Ana Romo, Tania Melina Rodríguez & Ricardo Alfredo Dewey

  3. RADBIO S.A.S., Sunchales, Argentina

    Ana Romo & Ricardo Alfredo Dewey

  4. Bio X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

    Guo Yu

  5. Centro de Medicina Traslacional (CEMET), Hospital de Alta Complejidad en Red “El Cruce” Nestor Carlos Kirchner, Florencio Varela, Argentina

    Ricardo Alfredo Dewey

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  1. Ana Romo
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Contributions

AR and RAD conceived and designed the study. AR, GY, and TMR performed the experiments and analyses. AR and RAD wrote the manuscript. All authors contributed to the manuscript revision and read and approved the submitted version.

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Correspondence to Ricardo Alfredo Dewey.

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Competing interests

TMR and RAD are co-inventors of the patent family “Isoform of the TGF-beta receptor II”, US10233227B2 (granted in the USA), EP3082846B1 (granted by the European Patent Office), ES2749615T3 (granted in Spain), and AR098827A1 (pending in Argentina). AR, TMR, and RAD are co-inventors on the patent application, “TGF-receptor II isoform, fusion peptide, methods of treatment, and methods in vitro,” US11072647B2 (granted in the United States) and pending in China (CN111100875A1), Australia (AU2019240609A1), Canada (Act 3.060.686), and Argentina (AR116885A1). Patents are owned by CONICET and Fundación Articular and were licensed to RAD BIO S.A.S. by the intellectual property license agreement 2019-890-APNDIR ♯CONICET. AR has shareholder equity in RAD BIO S.A.S., and RAD is a co-founder, and shareholder of RAD BIO S.A.S.

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Romo, A., Rodríguez, T.M., Yu, G. et al. Chimeric TβRII-SE/Fc overexpression by a lentiviral vector exerts strong antitumoral activity on colorectal cancer-derived cell lines in vitro and on xenografts. Cancer Gene Ther 31, 174–185 (2024). https://doi.org/10.1038/s41417-023-00694-z

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