20 maj 2025
Han et al. (BioRxiv)
Keywords
Iron metabolism
Macrophages
Bone metastasis
Erythroblast mimicry
Main Findings
Bone is a highly specialized organ that not only supports hematopoiesis but can also serve as a metastatic niche for disseminated tumor cells. Metastatic cells must overcome the bone marrow’s hypoxic, nutrient-limited conditions to establish secondary growth. While phenotypic mimicry of stromal cells has been proposed as an adaptive mechanism, the metabolic strategies tumor cells employ in this context remain poorly defined.
In a recent preprint, Han et al. provide compelling evidence that tumor cells engage in erythroblast mimicry to hijack iron from bone marrow macrophages and facilitate metastatic progression. Using a breast cancer bone metastasis model capable of in vivo metastatic niche labelling and single-cell RNA sequencing, the authors identified an iron-exporting macrophage population (iMACs) enriched in the metastatic niche that expresses Vcam1, Ccr3, and Cd163, along with transcriptional programs of Erythroblastic Island Macrophages (EIM). Notably, these cells were present under steady-state conditions and maintained their phenotype in the presence of metastases, suggesting they are pre-existing components of the bone marrow niche co-opted by cancer cells.
Given the clinical association between bone metastases and anemia, the study further examined erythropoiesis in metastatic bone marrow. The authors observed reduced erythrocyte numbers, decreased globin synthesis gene signature, and increased CD71 expression across erythroid progenitor stages—hallmarks of ineffective erythropoiesis linked to impaired iron availability. Importantly, metastatic cancer cells exhibited elevated expression of the hemoglobin subunit beta gene Hbband increased expression of the erythroid transcription factor Gata1 under hypoxic conditions. Knockdown of Gata1 in cancer cells diminished hemoglobin production and viability under hypoxia, directly implicating erythroid-like mimicry in tumor adaptation.
iMACs were positioned at tumor–stroma interphase, expressed high levels of the iron export protein ferroportin and located adjacent to CD71⁺ tumor cells. Functionally, iMACs supported tumor cell proliferation through iron transfer in co-culture experiments, and their depletion in vivousing JEDI T cells targeting the transcription factor Spic markedly reduced metastatic burden. This axis of iron transfer was further validated in human bone metastasis samples, underscoring its translational relevance.
This work sheds light on an unrecognized mechanism by which tumor cells exploit the erythropoietic architecture of the bone marrow to secure iron and promote both metastatic outgrowth and systemic anemia. By revealing this axis of erythroblast mimicry and iron acquisition, Han et al. open new avenues for targeting the metabolic crosstalk between tumor cells and the bone marrow microenvironment. Future mechanistic insights of this interaction may yield therapeutic strategies to disrupt bone metastasis and its associated hematologic complications.
Limitations
iMACs depletion using JETI T cells targeting Spic-EGFP shows a clear difference in decreasing metastatic burden in mice, however, it is unclear whether the antitumor effect is strictly restricted to iMACs depletion, or whether there is a contribution of cell death-induced inflammation that could potentially prevent metastatic spread, especially knowing that control mice do not presumably have similar rates of cell killing. It would be interesting to see whether Spic knockout mice which lack red pulp macrophages in the spleen (a resident macrophage population phenotypically and functionally similar to EIMs) also lack EIMs. If that is the case, then Spic KO mice would be a better model to study EIMs.
Another limitation of this study is the lack of a spontaneous metastasis tumor model that can mimic all epithelial-to-mesenchymal-transition steps which may be lacking in this study. Tumor cells that undergo EMT from the primary tumor may present phenotypic and functional differences compared to tumor cells injected I.V., thus, making conclusions drawn from studying the metastatic process incomplete. In addition, it would have been interesting to see whether Gata1deficient cancer cells result in a decreased metastatic burden in vivo. Lastly, it will be interesting to determine whether these findings can be recapitulated in other organs that harbor resident macrophage iron-recycling populations such as the liver (Kupffer cells) and the spleen (red-pulp macrophages).
Significance/Novelty
Although heme catabolizing macrophage promotion of metastasis is not a novel concept, tumor cell mimicry of erythroblasts to hijack macrophage is indeed novel. In addition, findings from this study are highly translational as they can result in the discovery of novel targetable pathways to disrupt metastasis and prevent cancer-associated anemia. Exploring potential targets from scRNAseq data generated from this study can generate new hypotheses and novel clinically relevant targets to disrupt metastatic spread.
Credit
Reviewed by Mehdi Chaib as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.
The author declares no conflict of interests in relation to their involvement in the review.