Whitman Matthew A, Mantri Madhav, Spanos Emmanuel, Estroff Lara A, De Vlaminck Iwijn, Fischbach Claudia
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA.
Department of Materials Science and Engineering, Cornell University, Ithaca, NY, 14850, USA; Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY, 14850, USA.
Biomaterials. 2025 Apr;315:122916. doi: 10.1016/j.biomaterials.2024.122916. Epub 2024 Oct 24.
Breast cancer bone metastasis is a major cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Moreover, mineralized biomaterials are commonly utilized for clinical bone defect repair, but how mineralized biomaterials affect the foreign body response and wound healing is unclear. Here, we investigate how bone mineral affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to bone mineral content depends on the murine tumor model used. While lack of bone mineral induces tumor-promoting microenvironments in both immunocompromised and immunocompetent animals, these changes are mediated by altered fibroblast phenotype in immunocompromised mice and macrophage polarization in immunocompetent mice. Collectively, our findings suggest that bone mineral density affects tumor growth by impacting microenvironmental complexity in an organism-dependent manner.
乳腺癌骨转移是晚期乳腺癌患者死亡的主要原因。尽管矿物质密度降低是骨转移的已知危险因素，但其潜在机制仍知之甚少，因为用传统方法研究骨矿物质密度对肿瘤异质性的单独影响具有挑战性。此外，矿化生物材料通常用于临床骨缺损修复，但矿化生物材料如何影响异物反应和伤口愈合尚不清楚。在这里，我们通过将单细胞RNA测序与含矿物质或不含矿物质的脱细胞骨基质相结合，研究骨矿物质如何在体内影响肿瘤生长和微环境复杂性。我们发现，骨矿物质的缺失显著影响成纤维细胞和免疫细胞的异质性，促进增加肿瘤生长并改变对损伤或疾病反应的表型。重要的是，我们观察到基质对骨矿物质含量的反应取决于所使用的小鼠肿瘤模型。虽然骨矿物质的缺乏在免疫受损和免疫健全的动物中均诱导促进肿瘤的微环境，但这些变化在免疫受损小鼠中由成纤维细胞表型改变介导，在免疫健全小鼠中由巨噬细胞极化介导。总的来说，我们的研究结果表明，骨矿物质密度通过以机体依赖的方式影响微环境复杂性来影响肿瘤生长。
