Dataset Information

Osteoclast-derived apoptotic bodies inhibit naive CD8⁺ T cell activation via Siglec15, promoting breast cancer secondary metastasis.

ABSTRACT: The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8⁺ T cell infiltrations and a higher survival rate. We uncover that the membranous Siglec15 on osteoclast-derived ABs binds with sialylated Toll-like receptor 2 (TLR2) and blocks downstream co-stimulatory signaling, leading to the inhibition of naive CD8⁺ T cell activation. In addition, our study shows that treatment with Siglec15 neutralizing antibodies significantly reduces the incidence of secondary metastases and improves the survival rate of mice with advanced breast cancer bone metastasis. Our findings reveal the immunosuppressive function of osteoclast-derived ABs in the bone-tumor niche and demonstrate the potential of Siglec15 as a common target for anti-resorption and immunotherapy.

SUBMITTER: Wu Y

PROVIDER: S-EPMC10518580 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Osteoclast-derived apoptotic bodies inhibit naive CD8<sup>+</sup> T cell activation via Siglec15, promoting breast cancer secondary metastasis.

Wu Yutong Y Ai Hongbo H Xi Yuhang Y Tan Jiulin J Qu Ying Y Xu Jianzhong J Luo Fei F Dou Ce C

Cell reports. Medicine 20230821 9

The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8<sup>+</sup> T cell infiltrations and a higher survival rate. We uncov ...[more]

PMID: 37607544

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Project description:Apoptotic bodies (ABs) traditionally considered as garbage bags that enclose residual components of dead cells are gaining increasing attentions due to their potential roles in intercellular communications. In bone turn over, at the end of bone resorption phase, most osteoclasts undergo apoptosis, generating large amounts of ABs. However, it remains unclear of the role of osteoclast-derived ABs in bone remodeling. Methods: Staurosporine (STS) was used to apoptotic induction and differential centrifugation was used to isolate ABs. Western blotting, flowcytometry and Transmission electron microscopy (TEM) were performed for ABs identification, while whole transcriptome of ABs from osteoclasts at different stages was detected by RNA-seq. VENN analysis and gene set enrichment analysis (GSEA) were performed to compare the profile similarities between ABs and parental cells. In vitro efficacy of ABs on angiogenesis and osteogenesis were evaluated by tube formation assay and ALP staining. In vivo, calvarial defect mice model was used to assess the effects of ABs-modified decalcified bone matrix (DBM) scaffolds on angiogenesis and osteogenesis. Results: Here we mapped the whole transcriptome paralleled with small RNA profiling of osteoclast derived ABs at distinct differentiation stages. Whole transcriptome analysis revealed significant differences in RNA signatures among the ABs generated from osteoclasts at different stages. By comparing with parental osteoclast RNA profiles, we found that the transcriptome of ABs exhibited high similarities with the corresponding parental cells. Functionally, in vitro and in vivo studies showed that similar with the parental cells, pOC-ABs potentiated endothelial progenitor cell proliferation and differentiation, whereas mOC-ABs promoted osteogenic differentiation. The inherited biological effects of ABs were shown mediated by several enriched lncRNAs of which the interference abolished AB functions. Conclusions: Our study revealed the total RNA profiles of osteoclast derived ABs and demonstrated their biological functions. Both gene set and functional analysis indicated that osteoclast derived ABs are biologically similar with the parental cells suggesting their bridging role in osteoclast-osteoblast coupling in bone remodeling.

Dataset Information

Osteoclast-derived apoptotic bodies inhibit naive CD8⁺ T cell activation via Siglec15, promoting breast cancer secondary metastasis.

Publications

Osteoclast-derived apoptotic bodies inhibit naive CD8<sup>+</sup> T cell activation via Siglec15, promoting breast cancer secondary metastasis.

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Dataset Information

Osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting breast cancer secondary metastasis.

Publications

Osteoclast-derived apoptotic bodies inhibit naive CD8<sup>+</sup> T cell activation via Siglec15, promoting breast cancer secondary metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Osteoclast-derived apoptotic bodies inhibit naive CD8⁺ T cell activation via Siglec15, promoting breast cancer secondary metastasis.