Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2.
Fiche publication
Date publication
mai 2023
Journal
International journal of molecular sciences
Auteurs
Membres identifiés du Cancéropôle Est :
Dr OREND Gertraud, Dr CARAPITO Raphaël
Tous les auteurs :
Gschwandtner M, Gammage AN, Deligne C, Mies LFM, Domaingo A, Murdamoothoo D, Loustau T, Schwenzer A, Derler R, Carapito R, Koch M, Mörgelin M, Orend G, Kungl AJ, Midwood KS
Lien Pubmed
Résumé
Bidirectional dialogue between cellular and non-cellular components of the tumor microenvironment (TME) drives cancer survival. In the extracellular space, combinations of matrix molecules and soluble mediators provide external cues that dictate the behavior of TME resident cells. Often studied in isolation, integrated cues from complex tissue microenvironments likely function more cohesively. Here, we study the interplay between the matrix molecule tenascin-C (TNC) and chemokine CCL2, both elevated in and associated with the progression of breast cancer and playing key roles in myeloid immune responses. We uncover a correlation between TNC/CCL2 tissue levels in HER2+ breast cancer and examine the physical and functional interactions of these molecules in a murine disease model with tunable TNC levels and in in vitro cellular and cell-free models. TNC supported sustained CCL2 synthesis, with chemokine binding to TNC via two distinct domains. TNC dominated the behavior of tumor-resident myeloid cells; CCL2 did not impact macrophage survival/activation whilst TNC facilitated an immune suppressive macrophage phenotype that was not dependent on or altered by CCL2 co-expression. Together, these data map new binding partners within the TME and demonstrate that whilst the matrix exerts transcriptional control over the chemokine, each plays a distinct role in subverting anti-tumoral immunity.
Mots clés
CCL2, MCP-1, breast cancer, extracellular matrix, macrophages, myeloid cells, tenascin-C
Référence
Int J Mol Sci. 2023 05 6;24(9):