Targeting the MAtrix REgulating MOtif abolishes several hallmarks of cancer, triggering antitumor immunity

• 成果类型: Article
• 署名作者: Li, Chengbei; Kaur, Amanpreet; Pavlidaki, Alexia; Spenle, Caroline; Rajnpreht, Irena; Donnadieu, Emmanuel; Salome, Nathalie; Molitor, Anne; Carapito, Raphael; Wack, Fanny; Erne, William; Lefebvre, Olivier; Averous, Gerlinde; Mitrentsi, Ioanna; Loustau, Thomas; Orend, Gertraud
• 署名单位: Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; CHU Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm); CHU Strasbourg; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9282
• DOI: 10.1073/pnas.2404485121
• 发表日期: 2024-10-15
• 关键词: epithelial-mesenchymal transition; human hepatoma-cells; tumor-growth; trail; metastasis; responses; invasion; icam-1; death

摘要

Tumor- targeted therapies have often been inefficient due to the lack of concomitant control over the tumor microenvironment. Using an immunocompetent autologous breast cancer model, we investigated a MAtrix REgulating MOtif (MAREMO)- mimicking peptide, which inhibits the protumorigenic extracellular matrix (ECM) molecule tenascin-C that activates several cancer hallmarks. In cultured cells, targeting the MAREMO blocks tenascin-C signaling involved in cell adhesion and immune- suppression by inhibiting tenascin-C interactions with fibronectin, TGFf3, CXCL12, and others, thereby blocking downstream events. Using RNASequencing and various genetic, molecular, in situ, and in vivo assays, we demonstrate that the MAREMO peptide similarly blocks multiple tenascin-C functions in vivo. This includes releasing tumor- infiltrating leukocytes, including CD8+ T cells, from the stroma. The MAREMO peptide also triggers interferon signaling, restoring antitumor immunity, contributing to tumor growth inhibition and reduced dissemination. The MAREMO peptide targets tumor cells directly by promoting growth suppression and inhibiting phenotypic plasticity, subsequently enhancing responsiveness to the endogenous death inducer tumor necrosis factor- related apoptosis- inducing ligand, as shown by a loss- of- function approach. Moreover, the MAREMO peptide largely subdues the tumor bed by depleting fibroblasts, repressing tenascin-C and other ECM molecules, and restoring the function of the few remaining blood vessels. In conclusion, targeting tenascin-C with a MAREMO peptide represents a powerful anticancer strategy with a broad inhibition of several cancer hallmarks.