Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages.

Sara Donzelli,Francesco Fazi,Enzo Gallo,Andrea Sacconi,Ilaria Iosue,Giovanni Blandino,Chiara Turco,Giulia Fontemaggi,Elisa Milano

doi:10.3390/cells9020418

Abstract

Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC.

Highlights

Macrophages, crucial players in the adaptive immune response, are usually involved in detection and destruction of pathogens and apoptotic cells; when recruited by breast cancer (BC) cells in the tumor stroma, macrophages actively participate in tumor progression
We recently reported that ID4 expression correlates with macrophage recruitment in triple-negative breast cancer (TNBC) [12]
We observed that TNBC tissues showing high macrophage infiltration, evaluated using CD68 as a macrophage marker, presented ID4 protein expression in cancer cells and in cells of the leukocyte infiltrate (Supplementary Figure S1)

Summary

Introduction

Macrophages, crucial players in the adaptive immune response, are usually involved in detection and destruction of pathogens and apoptotic cells; when recruited by breast cancer (BC) cells in the tumor stroma, macrophages actively participate in tumor progression. Tumor-associated macrophages (TAMs) are “educated”, through paracrine signaling from BC cells, to exert pro-angiogenic. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs through the downregulation of miR-107. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC

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