Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung

Abstract

Cancer metastasis is responsible for the clear majority of cancer-related deaths. Survival and expansion of cancer cells at secondary sites requires that these premetastatic microenvironments be primed by primary tumor cells and their secreted factors. Efforts to date have been limited by immune-deficient in vivo models and/or the need for finely-tuned analysis time points that reduce contributions from early-disseminating cancer cells. In this regard, we developed a tumor cell-free syngeneic breast cancer model for characterizing tumor cell secretome-mediated reprogramming of premetastatic tissues. We demonstrate that secretomes from metastatic breast cancer cells differentially regulate the lung and brain, promoting a tumor-supportive lung microenvironment with both elevated CD73 expression and decreased TNFα expression. Using in vitro models of CD73-positive mesenchymal stem cells (MSCs) and macrophages/monocytes, we tested whether MSCs can mediate anti-inflammatory effects of metastatic breast cancer cells. Notably, conditioned media from metastatic Py230 cells reprogrammed the secretomes of MSCs toward an anti-inflammatory state. Mining transcriptome data from Py8119 and Py230 cells revealed a lipocalin 2 (LCN2) axis that is selectively expressed in the metastatic Py230 cells, predicts poor breast cancer patient survival and is elevated in circulating serum of mice chronically treated with conditioned media from Py230 cells. Taken together, these results establish the utility of an immune-competent tumor cell-free model for characterizing the mechanisms of breast cancer cell priming of the premetastatic niche, demonstrate that MSCs can mediate the anti-inflammatory effects of metastatic breast cancer cells and substantiate LCN2 as a promising therapeutic target for blocking breast cancer progression.

Altered tumor microenvironment heterogeneity of penile cancer during progression from non‐lymphatic to lymphatic metastasis

“…Remodeling of the extracellular matrix, phenotypic alteration of resident epithelial cells, fibroblasts, and ECs, and an immunosuppressive microenvironment are central to generation of the premetastatic niche 38,66–68 and similar to the landscape observed in penile cancer in our study. Furthermore, the initial signals that have been reported to promote formation of the premetastatic niche include cancer‐derived mediators, most notably the S100 family genes and LCN2 , 69–71 which is also consistent with our findings.…”

Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer

“…To assess the feasibility of using TNBC lysates as antigen sources, we utilized three murine mammary carcinoma cell lines to recapitulate the heterogeneity of TNBC (57,58). Toward this end, we utilized Py230, a luminal cell line (59)(60)(61), and Py8119, a basal cell line (59)(60)(61), derived from the mouse mammary tumor virus−polyoma middle tumor antigen mouse model of breast cancer, which loses expression of estrogen and progesterone as it progresses (62). We chose the EMT6 cell line as a third model, as this syngeneic line has been recently recognized as a valuable model to study immune response in TNBC (63,64).…”

Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells via YAP signaling activation by exosomal Wnt5a

“…BM-MSCs possess tumor-tropic characteristics and incorporate into the tumor stroma to promote progression of malignant tumors. Interactions between MSCs and cancer cells are key drivers in this process [ 7 , 28 ], and highly malignant cancer cells display an enhanced ability to educate BM-MSCs [ 9 – 11 ]. Similar to the results obtained in previous studies, our results show that LNM-GCs, but not primary GCs, could reprogram BM-MSCs.…”

“…Xie et al found that the circulation time of BM-MSCs in mice with metastatic lung cancer was brief, and that BM-MSCs displayed increased metastatic tissue tropism [ 8 ]. Additionally, only cancer cells with higher metastatic capacity can trigger BM-MSC transition into-tumor-associated stromal cells [ 9 – 11 ]. Metastasis-associated MSCs are found in the metastatic LN and liver tissues of breast-cancer patients [ 12 ].…”