Reprogrammed macrophages promote spread of breast cancer

Reprogrammed macrophages promote spread of breast cancer
Transcriptomic analysis identifies characteristic changes in reactive ECs during metastatic colonization of the lung. a, Immunofluorescence images showing association of lung ECs (CD31) with metastatic breast cancer cells (GFP) in mouse lung at indicated time points post intravenous injection of MDA231-LM2 breast cancer cells. Scale bars, 50 μm. Dashed lines indicate margins of metastatic foci. b, Quantification of metastatic nodules from a with intranodular ECs; n = 72 nodules (week 1), n = 76 nodules (week 2) and n = 83 nodules (week 3) from four mice were analyzed for each time point. Data are presented as means ± s.e.m. c, Size of MDA231-LM2-derived metastatic nodules in lung at weeks 1–3. A minimum of 16 nodules were analyzed for each lung; n = 4 mice per group. d, MDA231-LM2 cancer cells (left) and ECs (right) in lung at indicated time points. Data show means ± s.d; n = 4 mice per time point. P values were determined by one-way ANOVA with Dunnett’s multiple comparison test. e, Experimental setup for EC isolation from mouse lung at different stages of MDA231-LM2-derived metastasis, followed by transcriptomic analysis. f, PC analysis of gene expression profiles from ECs isolated from healthy lung (control) or lung with different stages of metastasis (as in e). g, GSEA of isolated ECs using proliferation- or inflammation-related signatures. Signatures with nominal P < 0.05 and FDR < 0.25 were considered significant. h,i, Violin plots showing z-score analysis of tumor angiogenesis and tip cell signatures (h) or patient poor-outcome gene clusters (i), calculated from transcriptomic profiles of ECs isolated from metastatic lungs at indicated time points. P values were determined using averaged z-scores of each signature by unpaired two-tailed t-test; n = 3 biological replicates per group. j, Heatmap showing expression of 58 genes of secreted proteins (GSP58) upregulated in lung ECs at week 3 post cancer cell injection. Cutoff log2(fold change (FC)) > 0.75, P < 0.05, FDRq < 0.25. k, GSEA graph showing enrichment of GSP58 in samples of human lung metastases of breast cancer, ranked according to lung metastasis-free survival. NES, normalized enrichment score. FDR was determined from P values calculated by random permutation test. Credit: Nature Cancer (2022). DOI: 10.1038/s43018-022-00353-6

Metastatic breast cancer cells abuse macrophages, a type of immune cell, to promote the settlement of cancer metastases in the lungs. The reprogrammed macrophages stimulate blood vessel cells to secrete a cocktail of metastasis-promoting proteins that are part of the so-called metastatic niche. This was demonstrated by scientists from the German Cancer Research Center and the Stem Cell Institute HI-STEM in mice that had been transplanted with human breast cancer cells. The work enabled the scientists to identify new targets and develop initial concepts to better restrain the metastatic spread of breast cancer.

Cancer spreads within the body as detach from the and travel to distant body regions via the bloodstream or lymphatic system. Before they can grow into a metastasis at a secondary site, they must communicate with their new environment through a variety of molecular interactions. "In order to settle in this new, hostile milieu, the cancer cells corrupt the microenvironment to support their growth," says Thordur Oskarsson of the German Cancer Research Center (DKFZ) and the stem cell institute HI-STEM. Researchers refer to this as the creating a "metastatic niche."

Blood vessels play a very special role in metastasis. Detached tumor cells prefer to stay in their immediate vicinity. In particular, the interactions of cancer cells with the lining the inside of the vessels are crucial for metastasis, as many studies have already shown. However, the details of this molecular exchange are still largely unknown.

A team led by Oskarsson has now investigated these interactions during metastatic colonization of the lung by breast cancer cells in mice. The researchers first observed that four genes in the lung endothelial cells showed a particularly strong increase in activity three weeks after the onset of metastasis. They encode four proteins that are secreted into the microenvironment (Inhbb, Lama1, Scgb3a1 and Opg), which both individually and in combination promote the development of lung metastases. Inhbb and Scgb3a1 confer stem cell properties to cancer cells, Opg prevents programmed —apoptosis—and Lama1 supports adhesion-mediated . Importantly, high expression of these four newly identified niche factors correlates with both shortened relapse-free survival and shortened overall survival of breast cancer patients.

But how do cancer cells get the lung endothelium to produce the metastasis-promoting protein cocktail? To the surprise of the scientists, the cancer cells do not do this job directly themselves, but instead harness a cell type of the innate immune system for this purpose, the macrophages.

"These macrophages, which often reside in the vicinity of the lung , are activated by tenascin, an extracellular matrix protein produced by breast cancer cells," explains Tsunaki Hongu, the first author of the study. Tenascin is involved in disease progression in many cancers. After activation by tenascin, macrophages produce various factors that induce the production of the cancer-promoting protein cocktail in endothelial cells. By eliminating macrophages or their activity, using specific molecular agents, the investigators could show that these cells are crucial for production of the metastasis-promoting protein cocktail.

Oskarsson, who now works at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, summarizes: "The complexity of the crosstalk between , macrophages and endothelial cells is striking. With a better understanding of the numerous proteins and other factors involved in these metastatic interactions, we were able to identify a variety of starting points for new strategies against breast cancer metastasis. We have already developed initial therapeutic concepts for this, which we now need to validate in further studies."

The research was published in Nature Cancer.

More information: Thordur Oskarsson, Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs, Nature Cancer (2022). DOI: 10.1038/s43018-022-00353-6.

Journal information: Nature Cancer

Citation: Reprogrammed macrophages promote spread of breast cancer (2022, April 25) retrieved 24 March 2023 from
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