Targeting initial tumour–osteoclast spatiotemporal interaction to prevent bone metastasis (original) (raw)

Data availability

The main data that support the findings of this study are available within the paper and its Supplementary Information. The transcriptomic data of the OCPs, RA-OCPs, OCs and TAOCs can be found under accession no. PRJNA1045297. Further materials from this study are available from the corresponding author on reasonable request. Source Data are provided with this paper.

References

  1. Coleman, R. E. et al. Bone metastases. Nat. Rev. Dis. Prim. 6, 83 (2020).
    Article PubMed Google Scholar
  2. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).
    Article CAS PubMed Google Scholar
  3. von Moos, R. et al. Management of bone health in solid tumours: from bisphosphonates to a monoclonal antibody. Cancer Treat. Rev. 76, 57–67 (2019).
    Article Google Scholar
  4. Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).
    Article PubMed PubMed Central Google Scholar
  5. McAllister, S. S. & Weinberg, R. A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014).
    Article CAS PubMed PubMed Central Google Scholar
  6. Croucher, P. I., McDonald, M. M. & Martin, T. J. Bone metastasis: the importance of the neighbourhood. Nat. Rev. Cancer 16, 373–386 (2016).
    Article CAS PubMed Google Scholar
  7. Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).
    Article CAS PubMed PubMed Central Google Scholar
  8. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
    Article CAS PubMed Google Scholar
  9. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the Rosetta Stone of therapy resistance. Cancer Cell 37, 471–484 (2020).
    Article CAS PubMed PubMed Central Google Scholar
  10. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).
    Article CAS PubMed Google Scholar
  11. Ganesh, K. & Massagué, J. Targeting metastatic cancer. Nat. Med. 27, 34–44 (2021).
    Article CAS PubMed PubMed Central Google Scholar
  12. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
    Article PubMed Google Scholar
  13. Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J. Hematol. Oncol. 12, 76 (2019).
    Article PubMed PubMed Central Google Scholar
  14. Zhang, J. et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J. Clin. Invest. 107, 1235–1244 (2001).
    Article CAS PubMed PubMed Central Google Scholar
  15. Chen, Q., Zhang, X. H. & Massagué, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  16. Tsilimigras, D. I. et al. Liver metastases. Nat. Rev. Dis. Prim. 7, 27 (2021).
    Article PubMed Google Scholar
  17. Sevenich, L. et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014).
    Article CAS PubMed PubMed Central Google Scholar
  18. Hofbauer, L. C. et al. Novel approaches to target the microenvironment of bone metastasis. Nat. Rev. Clin. Oncol. 18, 488–505 (2021).
    Article PubMed Google Scholar
  19. Zhang, W. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 184, 2471–2486 (2021).
    Article CAS PubMed PubMed Central Google Scholar
  20. Satcher, R. L. & Zhang, X. H. F. Evolving cancer–niche interactions and therapeutic targets during bone metastasis. Nat. Rev. Cancer 22, 85–101 (2022).
    Article CAS PubMed Google Scholar
  21. Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  22. Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).
    Article CAS PubMed Google Scholar
  23. Ell, B. & Kang, Y. SnapShot: bone metastasis. Cell 151, 690 (2012).
    Article CAS PubMed Google Scholar
  24. Wu, K. et al. Exosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer. Nat. Commun. 12, 5196 (2021).
    Article CAS PubMed PubMed Central Google Scholar
  25. Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  26. Lin, X. et al. Smart nanosacrificial layer on the bone surface prevents osteoporosis through acid-base neutralization regulated biocascade effects. J. Am. Chem. Soc. 142, 17543–17556 (2020).
    Article CAS PubMed Google Scholar
  27. Perrin, D. D. Binding of tetracyclines to bone. Nature 208, 787–788 (1965).
    Article CAS PubMed Google Scholar
  28. Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).
    Article CAS PubMed Google Scholar
  29. McDonald, M. M. et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 184, 1330–1347 (2021).
    Article CAS PubMed PubMed Central Google Scholar
  30. Ell, B. et al. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24, 542–5556 (2013).
    Article CAS PubMed Google Scholar
  31. Jiao, H. et al. Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell 184, 2896–2910 (2021).
    Article CAS PubMed Google Scholar
  32. Hasegawa, T. et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 20, 1631–1643 (2019).
    Article CAS PubMed Google Scholar
  33. Chaffer, C. L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61–74 (2013).
    Article CAS PubMed PubMed Central Google Scholar
  34. Morel, A. P. et al. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat. Med. 23, 568–578 (2017).
    Article CAS PubMed Google Scholar
  35. Matsuo, K. et al. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat. Genet. 24, 184–187 (2000).
    Article CAS PubMed Google Scholar
  36. Jardine, L. et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature 598, 327–331 (2021).
    Article CAS PubMed PubMed Central Google Scholar
  37. Li, Z. et al. ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation. Nat. Commun. 13, 2011 (2022).
    Article CAS PubMed PubMed Central Google Scholar
  38. Miyazaki, T., Miyauchi, S., Anada, T., Imaizumi, H. & Suzuki, O. Evaluation of osteoclastic resorption activity using calcium phosphate coating combined with labeled polyanion. Anal. Biochem. 410, 7–12 (2011).
    Article CAS PubMed Google Scholar
  39. Wang, H. et al. Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies. Nat. Commun. 8, 15045 (2017).
    Article PubMed PubMed Central Google Scholar
  40. Wang, H. et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27, 193–210 (2015).
    Article PubMed PubMed Central Google Scholar
  41. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
  42. Ma, L. et al. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res. 25, 24–38 (2015).
    Article CAS PubMed Google Scholar
  43. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci USA 102, 15545–15550 (2005).
  44. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
  45. Keenan, A. B. et al. ChEA3: transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Res. 47, W212–W224 (2019).
  46. Tang, R. et al. Micro-computed tomography (Micro-CT): a novel approach for intraoperative breast cancer specimen imaging. Breast Cancer Res. Treat. 139, 311–316 (2013).
    Article PubMed Google Scholar

Download references

Acknowledgements

This work was supported by grants from the National Nature Science Fund of China (grant nos. 82322043, 92268113 and 82072414 to XF.L., 82372454 to PF.C. and 82330077 to S.F.), the Natural Science Fund of Zhejiang Province (grant no. LGF21H060005 to Y.H.), and the Zhejiang Provincial Department of Science and Technology “Leading Geese” research and development project (grant no. 2023C03091 to S.F.). We thank H. Jiao at the School of Life Sciences of Tsinghua University for his theoretical support on migrasome formation. We thank Q. Bian and Y. Zhou at the Zhejiang Province Key Laboratory of Anti-Cancer Drug Research for their technical support on animal experiments. We thank K. Kong at the Department of Chemistry of Zhejiang University for his theoretical support on CaP crystals. We thank L. Wu, P. Yang, D. Song and G. Zhu at the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for their technical assistance on cryo-TEM, TEM and SEM.

Author information

Author notes

  1. These authors contributed equally: Chenhui Gu, Pengfei Chen, Hongsen Tian.

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Chenhui Gu, Pengfei Chen, Hongsen Tian, Yang Yang, Zhenxiang Huang, Huige Yan, Liqing Shangguan, Kaifeng Pan, Pengyu Chen, Yue Huang, Shunwu Fan & Xianfeng Lin
  2. Key Laboratory of Mechanism Research and Precision Repair of Orthopaedic Trauma and Aging Diseases of Zhejiang Province, Hangzhou, China
    Chenhui Gu, Pengfei Chen, Hongsen Tian, Yang Yang, Zhenxiang Huang, Huige Yan, Liqing Shangguan, Kaifeng Pan, Pengyu Chen, Yue Huang, Shunwu Fan & Xianfeng Lin
  3. Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Chenxi Tang
  4. College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
    Jiajia Xiang
  5. Department of Chemistry, Zhejiang University, Hangzhou, China
    Zhaoming Liu & Ruikang Tang

Authors

  1. Chenhui Gu
  2. Pengfei Chen
  3. Hongsen Tian
  4. Yang Yang
  5. Zhenxiang Huang
  6. Huige Yan
  7. Chenxi Tang
  8. Jiajia Xiang
  9. Liqing Shangguan
  10. Kaifeng Pan
  11. Pengyu Chen
  12. Yue Huang
  13. Zhaoming Liu
  14. Ruikang Tang
  15. Shunwu Fan
  16. Xianfeng Lin

Contributions

C.G., PF.C. and XF.L. designed the project. C.G., PF.C., H.T., Y.Y., Z.H., H.Y., K.P. and PY.C. performed the experiments. C.T., J.X. and L.S. provided technical help. C.G. and H.Y. created the visualizations. C.G., PF.C., S.F. and XF.L. wrote the manuscript. XF.L. and S.F. supervised the project. All of the authors analysed and interpreted the data, and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence toShunwu Fan or Xianfeng Lin.

Ethics declarations

Competing interests

XF.L., C.G. and S.F. are on a patent application (CN 2024100072569) filed by Zhejiang University related to this work. The other authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Hiroki Yokota, Xiang (H.-F.) Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Schematic diagram of migrasome-mediated tumour-TAOC coupling interaction and behaviour-targeted strategy with decoupling–killing therapy by HC&HP@TNL.

Tumour cells induce spatially contacted RANKL-activated osteoclast precursor (RA-OCP) into “Tumasteoclast” (TAOC) to form tumour-TAOC spatiotemporal coupling interaction via migrasome-mediated cytoplasmic transfer. Based on the spatiotemporal characteristics of tumour-TAOC coupling in the initial metastasis, we constructed tetracycline-modified nanoliposomes encapsulating sodium bicarbonate and sodium hydrogen phosphate (HC&HP@TNL). When the bone metastasis reactivates and tumour-TAOC coupling is formed, HC&HP@TNL will be triggered by TAOC to release high concentrations of sodium hydrogen phosphate. Hydrogen phosphate combines with calcium ions in the microenvironment to form in situ calcium-phosphorus (CaP) crystals, which reduce the calcium concentration to inhibit migrasome formation, and disrupt the cell membrane integrity to induce immunogenic cell death (ICD) for immune response.

Extended Data Fig. 2 HC&HP@TNL activates the antitumour immune response.

a-c, Schematic representation of an ectopic injection model after CaP-treated 4T1 cell injection (a), distant mammary tumour image (b) and tumour volume (c) (scale bar, 10 mm, n = 8 independent mice, mean ± SD). d-f, Schematic representation of an ectopic injection model after bone metastasis treatment (d), distant mammary tumour image (e) and tumour volume (f) (scale bar, 10 mm, n = 8 independent mice, mean ± SD). g, Flow cytometric analysis of CD80 + CD86+ DCs in draining lymph nodes. h, i, Flow cytometric analysis of CD4 + T cells (h) and CD8 + T cells (i) in the distant mammary tumours (n = 6 independent mice, mean ± SD). j, HE staining and immunofluorescence images of CD8 and CD4 (scale bar, 100μm). k, Distant tumour volume in an ectopic injection model after CaP-treated 4T1 cell injection in immunocompromised mice (scale bar, 10 mm, n = 8 independent mice, mean ± SD). l, Distant tumour volume in an ectopic injection model after bone metastasis treatment in immunocompromised mice (scale bar, 10 mm, n = 4 independent mice for Cl@TNL as control, n = 8 independent mice for HC&HP@TNL, mean ± SD). m, Tumour volume of bone metastasis in BALB/c normal mice (n = 8 independent mice, mean ± SD) and immunocompromised mice (n = 4 independent mice for Cl@TNL, n = 7 independent mice for HC&HP@TNL, mean ± SD). n, Tumour inhibition rate of bone metastasis by HC&HP@TNL in normal BALB/c, immuno-enhanced BALB/c, and immunocompromised BALB/c (Cl@TNL as control of 0%, n = 8 independent mice for normal BALB/c and BALB/c+anti-PD-1, n = 7 independent mice for BALB/c-nu/nu, mean ± SD). o, Inhibition effect percent of CaP effect, ICD effect, and ICB effect in bone metastasis by HC&HP@TNL+anti-PD-1. (n = 8 independent mice, mean ± SD). P values were determined using two-way ANOVA with Šidák’s multiple-comparison test (c, f, k, l), or two-tailed one-way ANOVA with a Tukey post-hoc test (g-i, m-o).

Supplementary information

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article

Gu, C., Chen, P., Tian, H. et al. Targeting initial tumour–osteoclast spatiotemporal interaction to prevent bone metastasis.Nat. Nanotechnol. 19, 1044–1054 (2024). https://doi.org/10.1038/s41565-024-01613-5

Download citation