Bone serves as a transfer station for secondary dissemination of breast cancer

Schwarz, R. F. et al. Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. PLoS Med. 12, e1001789 (2015).

Hong, W. S., Shpak, M. & Townsend, J. P. Inferring the origin of metastases from cancer phylogenies. Cancer Res. 75, 4021–4025 (2015).

McFadden, D. G. et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 156, 1298–1311 (2014).

Obenauf, A. C. & Massague, J. Surviving at a distance: organ-specific metastasis. Trends Cancer 1, 76–91 (2015).

Minn, A. J. et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J. Clin. Investig. 115, 44–55 (2005).

Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

Hong, M. K. et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 6, 6605 (2015).

Ullah, I. et al. Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes. J. Clin. Investig. 128, 1355–1370 (2018).

Brown, D. et al. Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations. Nat. Commun. 8, 14944 (2017).

Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).

Coleman, R. E. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 12, 6243s–6249s (2006).

Domchek, S. M., Younger, J., Finkelstein, D. M. & Seiden, M. V. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 89, 363–368 (2000).

Esposito, M., Guise, T. & Kang, Y. The biology of bone metastasis. Cold Spring Harb. Perspect Med. 8, a031252 (2018).

Li, X. Q., Zhang, R., Lu, H., Yue, X. M. & Huang, Y. F. Extracellular vesicle-packaged CDH11 and ITGA5 induce the premetastatic niche for bone colonization of breast cancer cells. Cancer Res. 82, 1560–1574 (2022).

Zhang, W. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 184, 2471–2486 e2420 (2021).

Kennecke, H. et al. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 28, 3271–3277 (2010).

Kriege, M. et al. Distant disease-free interval, site of first relapse and post-relapse survival in BRCA1- and BRCA2-associated compared to sporadic breast cancer patients. Breast Cancer Res. Treat. 111, 303–311 (2008).

Coleman, R. E. & Rubens, R. D. The clinical course of bone metastases from breast cancer. Br. J. Cancer 55, 61–66 (1987).

Guth, U. et al. Primary and secondary distant metastatic breast cancer: two sides of the same coin. Breast 23, 26–32 (2014).

Coleman, R. E., Smith, P. & Rubens, R. D. Clinical course and prognostic factors following bone recurrence from breast cancer. Br. J. Cancer 77, 336–340 (1998).

Zhang, L., Zhang, J., Li, Z., Wu, Y. & Tong, Z. Comparison of the clinicopathological characteristics and prognosis between Chinese patients with breast cancer with bone-only and non-bone-only metastasis. Oncol. Lett. 20, 92 (2020).

Muscarella, A. M., Aguirre, S., Hao, X., Waldvogel, S. M. & Zhang, X. H. Exploiting bone niches: progression of disseminated tumor cells to metastasis. J. Clin. Investig. 131, e143764 (2021).

Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005).

Janni, W. et al. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse-a European pooled analysis. Clin. Cancer Res. 17, 2967–2976 (2011).

Bidard, F. C. et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin. Cancer Res. 14, 3306–3311 (2008).

Hartkopf, A. D. et al. Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients - results from a large single-centre analysis. Eur. J. Cancer 50, 2550–2559 (2014).

Braun, S., Auer, D. & Marth, C. The prognostic impact of bone marrow micrometastases in women with breast cancer. Cancer Investig. 27, 598–603 (2009).

Tjensvoll, K. et al. Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients. BMC Cancer 19, 1131 (2019).

Wiedswang, G. et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J. Clin. Oncol. 21, 3469–3478 (2003).

Goldvaser, H. & Amir, E. Role of bisphosphonates in breast cancer therapy. Curr. Treat. Options Oncol. 20, 26 (2019).

Byrne, N. M., Summers, M. A. & McDonald, M. M. Tumor cell dormancy and reactivation in bone: skeletal biology and therapeutic opportunities. JBMR 3, e10125 (2019).

Salvador, F., Llorente, A. & Gomis, R. R. From latency to overt bone metastasis in breast cancer: potential for treatment and prevention. J. Pathol. 249, 6–18 (2019).

Winter, M. C. & Coleman, R. E. Bisphosphonates in the adjuvant treatment of breast cancer. Clin. Oncol. 25, 135–145 (2013).

Eisen, A. et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: ASCO-OH (CCO) Guideline Update. J. Clin. Oncol. 40, 787–800 (2022).

Solomayer, E. F. et al. Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann. Oncol. 23, 2271–2277 (2012).

Banys, M. et al. Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 13, 480 (2013).

Aft, R. et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 11, 421–428 (2010).

Vidula, N. et al. Evaluation of disseminated tumor cells and circulating tumor cells in patients with breast cancer receiving adjuvant zoledronic acid. NPJ Breast Cancer 7, 113 (2021).

Hoffmann, O. et al. Effect of ibandronate on disseminated tumor cells in the bone marrow of patients with primary breast cancer: a pilot study. Anticancer Res. 31, 3623–3628 (2011).

Kokufu, I., Kohno, N., Yamamoto, M. & Takao, S. Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes. Oncol. Lett. 1, 247–252 (2010).

Powles, T. et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8, R13 (2006).

Powles, T. et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J. Clin. Oncol. 20, 3219–3224 (2002).

Hoffmann, O. et al. Evaluation of the prognostic significance of disseminated tumor cells in the bone marrow of primary, non-metastatic breast cancer patients after a 7-year follow-up. Arch. Gynecol. Obstet. 292, 1117–1125 (2015).

Kasimir-Bauer, S. et al. Different prognostic value of circulating and disseminated tumor cells in primary breast cancer: Influence of bisphosphonate intake? Sci. Rep. 6, 26355 (2016).

Ahn, S. G., Kim, S. H., Lee, H. M., Lee, S. A. & Jeong, J. Survival benefit of zoledronic acid in postmenopausal breast cancer patients receiving aromatase inhibitors. J. Breast Cancer 17, 350–355 (2014).

Early Breast Cancer Trialists’ Collaborative, G. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386, 1353–1361 (2015).

Carlson, P. et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat. Cell Biol. 21, 238–250 (2019).

Braun, S. et al. Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J. Clin. Oncol. 18, 80–86 (2000).

Naume, B. et al. Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer. J. Clin. Oncol. 32, 3848–3857 (2014).

Close, D., Xu, T., Ripp, S. & Sayler, G. Real-time bioluminescent tracking of cellular population dynamics. Methods Mol. Biol. 1098, 107–116 (2014).

de Almeida, P. E., van Rappard, J. R. & Wu, J. C. In vivo bioluminescence for tracking cell fate and function. Am. J. Physiol. Heart Circ. Physiol. 301, H663–H671 (2011).

Moriyama, E. H. et al. The influence of hypoxia on bioluminescence in luciferase-transfected gliosarcoma tumor cells in vitro. Photochem Photobio. Sci. 7, 675–680 (2008).

O’Neill, K., Lyons, S. K., Gallagher, W. M., Curran, K. M. & Byrne, A. T. Bioluminescent imaging: a critical tool in pre-clinical oncology research. J. Pathol. 220, 317–327 (2010).

Weissleder, R. A clearer vision for in vivo imaging. Nat. Biotechnol. 19, 316–317 (2001).

Contag, C. H. et al. Photonic detection of bacterial pathogens in living hosts. Mol. Microbiol/ 18, 593–603 (1995).

Degano, I. R. et al. Bioluminescence imaging of calvarial bone repair using bone marrow and adipose tissue-derived mesenchymal stem cells. Biomaterials 29, 427–437 (2008).

Kalhor, R., Mali, P. & Church, G. M. Rapidly evolving homing CRISPR barcodes. Nat. Methods 14, 195–200 (2017).

Kalhor, R. et al. Developmental barcoding of whole mouse via homing CRISPR. Science 361, eaat9804 (2018).

Kang, Y. & Kuperwasser, C. Evolving barcodes shed light into evolving metastases. Dev. Cell 56, 1077–1079 (2021).

Conboy, M. J., Conboy, I. M. & Rando, T. A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013).

Eggel, A. & Wyss-Coray, T. A revival of parabiosis in biomedical research. Swiss Med Wkly 144, w13914 (2014).

Rando, T. A. & Chang, H. Y. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46–57 (2012).

Molodtsov, A. K. et al. Resident memory CD8(+) T cells in regional lymph nodes mediate immunity to metastatic melanoma. Immunity 54, 2117–2132 e2117 (2021).

Burbach, B. J. et al. Irreversible electroporation augments checkpoint immunotherapy in prostate cancer and promotes tumor antigen-specific tissue-resident memory CD8+ T cells. Nat. Commun. 12, 3862 (2021).

Feng, N., Luo, J. M. & Guo, X. The immune influence of a parabiosis model on tumour-bearing mice. Swiss Med Wkly 148, w14678 (2018).

Ayasoufi, K. et al. Brain cancer induces systemic immunosuppression through release of non-steroid soluble mediators. Brain 143, 3629–3652 (2020).

Pradeep, S. et al. Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell 26, 77–91 (2014).

Duyverman, A. M., Kohno, M., Duda, D. G., Jain, R. K. & Fukumura, D. A transient parabiosis skin transplantation model in mice. Nat. Protoc. 7, 763–770 (2012).

Yang, C. et al. Parabiosis modeling: protocol, application and perspectives. Zool. Res 42, 253–261 (2021).

Li, X. Q. et al. ITGBL1 Is a Runx2 transcriptional target and promotes breast cancer bone metastasis by activating the TGFbeta signaling pathway. Cancer Res 75, 3302–3313 (2015).

Taipaleenmaki, H. et al. Targeting of Runx2 by miR-135 and miR-203 impairs progression of breast cancer and metastatic bone disease. Cancer Res 75, 1433–1444 (2015).

Wang, W. et al. Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells. Clin. Exp. Metastasis 33, 475–485 (2016).

Tian, Z. et al. Harnessing the power of antibodies to fight bone metastasis. Sci. Adv. 7, eabf2051 (2021).

Borriello, L., Condeelis, J., Entenberg, D. & Oktay, M. H. Breast cancer cell re-dissemination from lung metastases-a mechanism for enhancing metastatic burden. J. Clin. Med. 10, 2340 (2021).

Vitos, N. & Gerlee, P. Model-based inference of metastatic seeding rates in de novo metastatic breast cancer reveals the impact of secondary seeding and molecular subtype. Sci. Rep. 12, 9455 (2022).

Satcher, R. L. & Zhang, X. H. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Nat. Rev. Cancer 22, 85–101 (2022).

Gkountela, S. et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell 176, 98–112 e114 (2019).

Hamza, B. et al. Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice. Nat. Commun. 12, 5680 (2021).

Scheidmann, M. C. et al. An in vivo CRISPR screen identifies stepwise genetic dependencies of metastatic progression. Cancer Res. 82, 681–694 (2022).

Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

Comen, E. & Norton, L. Self-seeding in cancer. Recent Results Cancer Res. 195, 13–23 (2012).

Liu, T. et al. Self-seeding circulating tumor cells promote the proliferation and metastasis of human osteosarcoma by upregulating interleukin-8. Cell Death Dis. 10, 575 (2019).

Wang, S. et al. FOXF2 reprograms breast cancer cells into bone metastasis seeds. Nat. Commun. 10, 2707 (2019).

Balic, M. et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 12, 5615–5621 (2006).

Alix-Panabieres, C. et al. Detection and characterization of putative metastatic precursor cells in cancer patients. Clin. Chem. 53, 537–539 (2007).

Ling, L. J. et al. A novel mouse model of human breast cancer stem-like cells with high CD44+CD24-/lower phenotype metastasis to human bone. Chin. Med J. 121, 1980–1986 (2008).

Bado, I. L. et al. The bone microenvironment increases phenotypic plasticity of ER(+) breast cancer cells. Dev. Cell 56, 1100–1117 e1109 (2021).

Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

Tayoun, T. et al. CTC-derived models: a window into the seeding capacity of circulating tumor cells (CTCs). Cells 8, 1145 (2019).

Liu, T. et al. Circulating glioma cells exhibit stem cell-like properties. Cancer Res. 78, 6632–6642 (2018).

Luo, C. et al. Biomaterial-based platforms for cancer stem cell enrichment and study. Cancer Biol. Med. 18, 458–469 (2021).

Price, T. T. et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci. Transl. Med. 8, 340ra373 (2016).

Jiang, H. et al. Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1. Nat. Commun. 11, 5129 (2020).

Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

Sandiford, O. A. et al. Mesenchymal stem cell-secreted extracellular vesicles instruct stepwise dedifferentiation of breast cancer cells into dormancy at the bone marrow perivascular region. Cancer Res. 81, 1567–1582 (2021).

Bartosh, T. J., Ullah, M., Zeitouni, S., Beaver, J. & Prockop, D. J. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc. Natl. Acad. Sci. USA 113, E6447–E6456 (2016).

Bliss, S. A. et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res 76, 5832–5844 (2016).

Patel, S. A. et al. Treg/Th17 polarization by distinct subsets of breast cancer cells is dictated by the interaction with mesenchymal stem cells. J. Cancer Stem Cell Res. 2014, e1003 (2014).

Mishra, P. J. et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68, 4331–4339 (2008).

Momin, E. N., Vela, G., Zaidi, H. A. & Quinones-Hinojosa, A. The oncogenic potential of mesenchymal stem cells in the treatment of cancer: directions for future research. Curr. Immunol. Rev. 6, 137–148 (2010).

Wang, H. et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27, 193–210 (2015).

Wang, H., Yu, C. & Zhang, X. H. Devil’s Wake: Early-stage bone colonization by breast cancer. Mol. Cell Oncol. 3, e1026526 (2016).

Wang, H. et al. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell 34, 823–839 e827 (2018).

Li, X. Q., Lu, J. T., Tan, C. C., Wang, Q. S. & Feng, Y. M. RUNX2 promotes breast cancer bone metastasis by increasing integrin alpha5-mediated colonization. Cancer Lett. 380, 78–86 (2016).

Pantano, F. et al. Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions. Oncogene 40, 1284–1299 (2021).

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).

Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 (2017).

Riquelme, M. A., Cardenas, E. R. & Jiang, J. X. Osteocytes and bone metastasis. Front. Endocrinol. (Lausanne) 11, 567844 (2020).

Chang, C. J. et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 19, 86–100 (2011).

Zagorac, S. et al. SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells. Cancer Res. 81, 580–593 (2021).

Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).

Russo, S., Scotto di Carlo, F. & Gianfrancesco, F. The osteoclast traces the route to bone tumors and metastases. Front. Cell Dev. Biol. 10, 886305 (2022).

Tahara, R. K., Brewer, T. M., Theriault, R. L. & Ueno, N. T. Bone metastasis of breast cancer. Adv. Exp. Med Biol. 1152, 105–129 (2019).

Nakai, Y. et al. Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis. Bone Res. 7, 1 (2019).

Ferrer, A. et al. Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy. Cancer Lett. 488, 9–17 (2020).

Mayhew, V., Omokehinde, T. & Johnson, R. W. Tumor dormancy in bone. Cancer Rep. 3, e1156 (2020).

Wang, C. H. et al. Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties. Oncogene 37, 589–600 (2018).

Yoo, K. H. & Hennighausen, L. EZH2 methyltransferase and H3K27 methylation in breast cancer. Int. J. Biol. Sci. 8, 59–65 (2012).

Li, J. et al. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat. Neurosci. 16, 1745–1753 (2013).

Mandhair, H. K., Novak, U. & Radpour, R. Epigenetic regulation of autophagy: a key modification in cancer cells and cancer stem cells. World J. Stem Cells 13, 542–567 (2021).

Robinson, N. J., Parker, K. A. & Schiemann, W. P. Epigenetic plasticity in metastatic dormancy: mechanisms and therapeutic implications. Ann. Transl. Med. 8, 903 (2020).

Kim, I. & Park, J. W. Hypoxia-driven epigenetic regulation in cancer progression: a focus on histone methylation and its modifying enzymes. Cancer Lett. 489, 41–49 (2020).

Kfoury, Y. et al. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell 39, 1464–1478 e1468 (2021).

Reinstein, Z. Z. et al. Overcoming immunosuppression in bone metastases. Crit. Rev. Oncol. Hematol. 117, 114–127 (2017).

Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).

Uckun, F. M. Overcoming the immunosuppressive tumor microenvironment in multiple myeloma. Cancers 13, 2018 (2021).

Glatman Zaretsky, A. et al. T regulatory cells support plasma cell populations in the bone marrow. Cell Rep. 18, 1906–1916 (2017).

Long, H. et al. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell 40, 674–693 (2022).

Wu, W. C. et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc. Natl. Acad. Sci. USA 111, 4221–4226 (2014).

Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32, 790–802 (2010).

Solito, S. et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118, 2254–2265 (2011).

Consonni, F. M. et al. Myeloid-derived suppressor cells: ductile targets in disease. Front. Immunol. 10, 949 (2019).

Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).

Zhao, L. et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat. Med. 24, 1536–1544 (2018).

Meng, J. et al. Tumor-derived Jagged1 promotes cancer progression through immune evasion. Cell Rep. 38, 110492 (2022).

Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

Werner-Klein, M. & Klein, C. A. Therapy resistance beyond cellular dormancy. Nat. Cell Biol. 21, 117–119 (2019).