journal contribution posted on 2023-03-31, 01:45 authored by Amanda Valeta-Magara, Abhilash Gadi, Viviana Volta, Beth Walters, Rezina Arju, Shah Giashuddin, Hua Zhong, Robert J. Schneider
FS1: Four panels (A-D) demonstrating that SUM190 cells are enriched in cancer stem-like cells, shown by immunoblot analysis, cell flow cytometry and by increased cell invasion. FS2: Three panels (A-C) showing that co-culture of IBC cells with monocytes-macrophages increases IBC cell mesenchymal characteristics, shown by immunoblot analysis and invasion assays. FS3: Three immunoblot panels showing that addition of IL8 and GRO cytokines to the media of IBC cells promotes phosphorylation of STAT3 and cancer stem cell-like and mesenchymal characteristics. FS4: Four panels showing that IBC cells secrete attracting and type II polarization factors for monocytes and macrophages. Shown by function assays, cytokine sandwich blot assays, flow cytometry and immunohistochemistry.
Howard Hughes Medical Institute
Breast Cancer Research Foundation
ARTICLE ABSTRACTInflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages. The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft model of IBC, we demonstrate that IBC strongly expresses IL8 and growth-regulated oncogene (GRO) chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine–paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer.
This study uncovers a signaling network in which IBC cells commandeer macrophages to become tumor-promoting, and they in turn drive IBC cells to be more cancer stem-like, mesenchymal, and aggressive.