Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
15 Aug 2024
15 Aug 2024
Historique:
received:
23
08
2023
accepted:
11
07
2024
medline:
16
8
2024
pubmed:
16
8
2024
entrez:
15
8
2024
Statut:
aheadofprint
Résumé
Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-β (LTβ) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTβ promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTβ activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTβ signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumours. Our findings highlight LTβ as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.
Identifiants
pubmed: 39147874
doi: 10.1038/s41556-024-01478-9
pii: 10.1038/s41556-024-01478-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81972462
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81772981
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Esposito, M., Guise, T. & Kang, Y. The biology of bone metastasis. Cold Spring Harb. Perspect. Med. 8, a031252 (2018).
pubmed: 29101110
pmcid: 5980796
doi: 10.1101/cshperspect.a031252
Zhang, W. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 184, 2471–2486.e20 (2021).
pubmed: 33878291
pmcid: 8087656
doi: 10.1016/j.cell.2021.03.011
Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).
pubmed: 18097410
pmcid: 3090667
doi: 10.1038/nature06385
Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005).
pubmed: 16120859
doi: 10.1056/NEJMoa050434
Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747.e6 (2017).
pubmed: 29232552
pmcid: 5729937
doi: 10.1016/j.ccell.2017.11.002
Wang, H. et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27, 193–210 (2015).
pubmed: 25600338
pmcid: 4326554
doi: 10.1016/j.ccell.2014.11.017
Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α
pubmed: 22137794
pmcid: 3241854
doi: 10.1016/j.ccr.2011.11.002
Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).
pubmed: 23728425
pmcid: 3826912
doi: 10.1038/ncb2767
Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).
pubmed: 9916131
pmcid: 407876
doi: 10.1172/JCI3523
Ross, M. H. et al. Bone-induced expression of integrin β
pubmed: 28855208
pmcid: 5841166
doi: 10.1158/0008-5472.CAN-17-1225
Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).
pubmed: 21295524
pmcid: 3040415
doi: 10.1016/j.ccr.2010.12.022
Satcher, R. L. & Zhang, X. H. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Nat. Rev. Cancer 22, 85–101 (2022).
pubmed: 34611349
doi: 10.1038/s41568-021-00406-5
Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).
pubmed: 26791720
pmcid: 5029466
doi: 10.1038/nature17038
Minn, A. J. et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J. Clin. Invest. 115, 44–55 (2005).
pubmed: 15630443
pmcid: 539194
doi: 10.1172/JCI22320
Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).
pubmed: 12842083
doi: 10.1016/S1535-6108(03)00132-6
Lelekakis, M. et al. A novel orthotopic model of breast cancer metastasis to bone. Clin. Exp. Metastasis 17, 163–170 (1999).
pubmed: 10411109
doi: 10.1023/A:1006689719505
Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
pubmed: 21399628
pmcid: 4504184
doi: 10.1038/nature09807
Picelli, S. et al. Full-length RNA-seq from single cells using Smart-seq2. Nat. Protoc. 9, 171–181 (2014).
pubmed: 24385147
doi: 10.1038/nprot.2014.006
Wang, X. L., He, Y., Zhang, Q. M., Ren, X. W. & Zhang, Z. M. Direct comparative analyses of 10X Genomics chromium and Smart-seq2. Genom. Proteom. Bioinf. 19, 253–266 (2021).
doi: 10.1016/j.gpb.2020.02.005
Reid, J. E. & Wernisch, L. Pseudotime estimation: deconfounding single cell time series. Bioinformatics 32, 2973–2980 (2016).
pubmed: 27318198
pmcid: 5039927
doi: 10.1093/bioinformatics/btw372
Jolly, M. K., Ware, K. E., Gilja, S., Somarelli, J. A. & Levine, H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol. 11, 755–769 (2017).
pubmed: 28548345
pmcid: 5496498
doi: 10.1002/1878-0261.12083
Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
pubmed: 19945376
doi: 10.1016/j.cell.2009.11.007
Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).
pubmed: 16049480
pmcid: 1283098
doi: 10.1038/nature03799
Lanczky, A. & Gyorffy, B. Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. J. Med. Internet Res. 23, e27633 (2021).
pubmed: 34309564
pmcid: 8367126
doi: 10.2196/27633
Rose, A. A. et al. Osteoactivin promotes breast cancer metastasis to bone. Mol. Cancer Res. 5, 1001–1014 (2007).
pubmed: 17951401
doi: 10.1158/1541-7786.MCR-07-0119
Maric, G., Rose, A. A., Annis, M. G. & Siegel, P. M. Glycoprotein non-metastatic b (GPNMB): a metastatic mediator and emerging therapeutic target in cancer. Onco Targets Ther. 6, 839–852 (2013).
pubmed: 23874106
pmcid: 3711880
Tang, X. et al. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway. Cancer Res. 73, 6206–6218 (2013).
pubmed: 24008316
doi: 10.1158/0008-5472.CAN-13-1049
Lu, T. T. & Browning, J. L. Role of the lymphotoxin/LIGHT system in the development and maintenance of reticular networks and vasculature in lymphoid tissues. Front. Immunol. 5, 47 (2014).
pubmed: 24575096
pmcid: 3920476
doi: 10.3389/fimmu.2014.00047
Haybaeck, J. et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295–308 (2009).
pubmed: 19800575
pmcid: 4422166
doi: 10.1016/j.ccr.2009.08.021
Bauer, J. et al. Lymphotoxin, NF-kB, and cancer: the dark side of cytokines. Dig. Dis. 30, 453–468 (2012).
pubmed: 23108301
doi: 10.1159/000341690
Das, R. et al. Lymphotoxin-β receptor–NIK signaling induces alternative RELB/NF-κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer. Mol. Carcinog. 58, 411–425 (2019).
pubmed: 30488488
doi: 10.1002/mc.22938
Garrett, I. R. et al. Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. N. Engl. J. Med. 317, 526–532 (1987).
pubmed: 3497347
doi: 10.1056/NEJM198708273170902
Shultz, L. D., Ishikawa, F. & Greiner, D. L. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 7, 118–130 (2007).
pubmed: 17259968
doi: 10.1038/nri2017
Johnson, R. W. et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat. Cell Biol. 18, 1078–1089 (2016).
pubmed: 27642788
pmcid: 5357601
doi: 10.1038/ncb3408
Wan, L. et al. MTDH–SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors. Cancer Cell 26, 92–105 (2014).
pubmed: 24981741
pmcid: 4101059
doi: 10.1016/j.ccr.2014.04.027
Nobre, A. R. et al. Bone marrow NG2
pubmed: 34993493
pmcid: 8730384
doi: 10.1038/s43018-021-00179-8
Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2, 141–150 (2008).
pubmed: 18371435
doi: 10.1016/j.stem.2007.11.014
Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).
pubmed: 9108485
doi: 10.1016/S0092-8674(00)80209-3
Hu, K. & Olsen, B. R. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J. Clin. Invest. 126, 509–526 (2016).
pubmed: 26731472
pmcid: 4731163
doi: 10.1172/JCI82585
Shupp, A. B., Kolb, A. D., Mukhopadhyay, D. & Bussard, K. M. Cancer metastases to bone: concepts, mechanisms, and interactions with bone osteoblasts. Cancers (Basel) 10, 182 (2018).
pubmed: 29867053
doi: 10.3390/cancers10060182
Upadhyay, V. & Fu, Y. X. Lymphotoxin signalling in immune homeostasis and the control of microorganisms. Nat. Rev. Immunol. 13, 270–279 (2013).
pubmed: 23524463
pmcid: 3900493
doi: 10.1038/nri3406
Hultgren, O., Eugster, H. P., Sedgwick, J. D., Korner, H. & Tarkowski, A. TNF/lymphotoxin-α double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. J. Immunol. 161, 5937–5942 (1998).
pubmed: 9834074
doi: 10.4049/jimmunol.161.11.5937
Roach, D. R. et al. Secreted lymphotoxin-α is essential for the control of an intracellular bacterial infection. J. Exp. Med. 193, 239–246 (2001).
pubmed: 11208864
pmcid: 2193339
doi: 10.1084/jem.193.2.239
Ehlers, S. et al. The lymphotoxin β receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J. Immunol. 170, 5210–5218 (2003).
pubmed: 12734369
doi: 10.4049/jimmunol.170.10.5210
Madge, L. A., Kluger, M. S., Orange, J. S. & May, M. J. Lymphotoxin-α
pubmed: 18292573
doi: 10.4049/jimmunol.180.5.3467
Binder, N. B. et al. Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis. Nat. Med. 15, 417–424 (2009).
pubmed: 19330010
doi: 10.1038/nm.1945
Lee, J. W. et al. The HIV co-receptor CCR5 regulates osteoclast function. Nat. Commun. 8, 2226 (2017).
pubmed: 29263385
pmcid: 5738403
doi: 10.1038/s41467-017-02368-5
Wilkinson, A. C. et al. Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature 571, 117–121 (2019).
pubmed: 31142833
pmcid: 7006049
doi: 10.1038/s41586-019-1244-x
Romero-Moreno, R. et al. The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis. Nat. Commun. 10, 4404 (2019).
pubmed: 31562303
pmcid: 6765048
doi: 10.1038/s41467-019-12108-6
Stashenko, P., Dewhirst, F. E., Peros, W. J., Kent, R. L. & Ago, J. M. Synergistic interactions between interleukin 1, tumor necrosis factor, and lymphotoxin in bone resorption. J. Immunol. 138, 1464–1468 (1987).
pubmed: 3492553
doi: 10.4049/jimmunol.138.5.1464
Andrews, S. FastQC: a quality control tool for high throughput sequence data. Babraham Bioinformatics http://www.bioinformatics.babraham.ac.uk/projects/fastqc/ (2010).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Danecek, P. et al. Twelve years of SAMtools and BCFtools. Gigascience 10, giab008 (2021).
pubmed: 33590861
pmcid: 7931819
doi: 10.1093/gigascience/giab008
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e21 (2019).
pubmed: 31178118
pmcid: 6687398
doi: 10.1016/j.cell.2019.05.031
Yu, G., Wang, L. G., Han, Y. & He, Q. Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).
pubmed: 22455463
pmcid: 3339379
doi: 10.1089/omi.2011.0118
Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).
pubmed: 24658644
pmcid: 4122333
doi: 10.1038/nbt.2859
Apweiler, R. et al. UniProt: the Universal Protein knowledgebase. Nucleic Acids Res. 32, D115–D119 (2004).
pubmed: 14681372
pmcid: 308865
doi: 10.1093/nar/gkh131
Cante-Barrett, K. et al. Lentiviral gene transfer into human and murine hematopoietic stem cells: size matters. BMC Res. Notes 9, 312 (2016).
pubmed: 27306375
pmcid: 4910193
doi: 10.1186/s13104-016-2118-z
Green, M. R. & Sambrook, J. Preparation of genomic DNA from mouse tails and other small samples. Cold Spring Harb. Protoc. 2017, pdb.prot093518 (2017).
pubmed: 28864567
doi: 10.1101/pdb.prot093518
Colic, M. et al. Identifying chemogenetic interactions from CRISPR screens with drugZ. Genome Med. 11, 52 (2019).
pubmed: 31439014
pmcid: 6706933
doi: 10.1186/s13073-019-0665-3
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Meng, J. et al. Tumor-derived Jagged1 promotes cancer progression through immune evasion. Cell Rep. 38, 110492 (2022).
pubmed: 35263601
doi: 10.1016/j.celrep.2022.110492
Wilkinson, A. C., Ishida, R., Nakauchi, H. & Yamazaki, S. Long-term ex vivo expansion of mouse hematopoietic stem cells. Nat. Protoc. 15, 628–648 (2020).
pubmed: 31915389
pmcid: 7206416
doi: 10.1038/s41596-019-0263-2
Cao, X. et al. Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance. Nat. Commun. 12, 5866 (2021).
pubmed: 34620867
pmcid: 8497482
doi: 10.1038/s41467-021-26112-2
Kos, C. H. et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J. Clin. Invest. 111, 1021–1028 (2003).
pubmed: 12671051
pmcid: 152589
doi: 10.1172/JCI17416