Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2

Abstract

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.

Chemokine Binding to Tenascin-C Influences Chemokine-Induced Immune Cell Migration

“…Due to their involvement in the same diseases, we have asked ourselves whether TNC affects chemokine-induced immune cell mobilization and what role GAGs play in this scenario [84]. Understanding these interactions is of high therapeutic relevance since a better insight into the chemokine interaction network will allow for better therapeutic strategies when certain chemokines can be targeted to fight cancer and chronic inflammatory diseases (for which many clinical studies have failed in the past).…”

Targeting Macrophages as a Novel Therapy to Treat Triple-Negative Breast Cancer: A Literature Review

“…The ECM can also act as a reservoir for soluble factors such as chemokines, which can explain why CCL2 plays such a pivotal role in TAM recruitment. CCL2, a chemokine that is highly secreted by tumour cells, has a major role in the recruitment of monocytes, macrophages, T-cells, Bcells, and other immune cells [17]. The use of anti-CCL2 antibodies in breast cancer models has shown varying results.…”