Li et al. investigated the in vivo activity of a peptide (MP5) that blocks the protumorigenic ECM molecule tenascin-C. MP5 slowed tumor growth in an orthotopic breast cancer model and promoted an epithelial cell phenotype, including a reduction in EMT genes. MP5 also upregulated IFNγ response genes; in particular, TRAIL was required for maximal efficacy in vivo. MP5 reduced expression of ECM, angiogenesis, TGFβ, and hypoxia gene sets, and decreased tumor fibroblasts and CD31+ endothelial cells. While immune cells in control tumors were confined to the stroma,treated tumors had more abundant CD11c+ DCs and CD8+ T cells t throughout.
Contributed by Morgan Janes
ABSTRACT: 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, TGFβ, 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.
Author Info: (1) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 6709
Author Info: (1) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (2) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (3) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (4) école Supérieure de Biotechnologie de Strasbourg (ESBS) UMR 7242, Groupe Peptide Thérapeutique, University of Strasbourg, Illkirch 67400, France. (5) Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris 75014, France. (6) Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris 75014, France. (7) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (8) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg 67091, France. (9) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg 67091, France. (10) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (11) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France. (12) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France. (13) Département de Pathologie, University Hospital Strasbourg, Strasbourg 67200, France. (14) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (15) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. University of Strasbourg, Institut Universitaire Technologique (IUT) Louis Pasteur, Schiltigheim 67300, France. (16) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France.
