Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Implantable pre-metastatic niches for the study of the microenvironmental regulation of disseminated human tumour cells

Abstract

Survivors of cancer often carry disseminated tumour cells (DTCs); however, they do not relapse from treatment owing to DTC dormancy. Understanding how the local microenvironment regulates the transition of DTCs from a quiescent state to active proliferation could suggest new therapeutic strategies to prevent or delay the formation of metastases. Here, we show that implantable biomaterial microenvironments incorporating human stromal cells, immune cells and cancer cells can be used to examine the post-dissemination phase of tumour microenvironment evolution. After subdermal implantation in mice, porous hydrogel scaffolds seeded with human bone marrow stromal cells form a vascularized niche and recruit human circulating tumour cells released from an orthotopic prostate tumour xenograft. Systemic injection of human peripheral blood mononuclear cells slowed the progression of early metastatic niches. However, the rate of overt metastases did not change. Implantable pre-metastatic niches provide a new opportunity to study DTC activation and evolution to lethal metastasis, and could facilitate the development of effective anti-metastatic therapies.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Subdermally implanted hBMSC-seeded ICC hydrogel scaffolds develop vascularized humanized niches in immunodeficient NSG mice.
Fig. 2: Humanized implantable microenvironments recapitulate tumour cell receptive and supportive functions of the pre-metastatic niche.
Fig. 3: Implantable humanized stromal niches attract systemic hPBMCs.
Fig. 4: Instigation of humanized pre-metastatic niches with hPBMCs and long-term monitoring of DTC niche evolution via serial transplantation.
Fig. 5: Detection of rare dormant DTCs via whole scaffold tissue clearing and optical sectioning.
Fig. 6: Quantitative comparison of vascular, stromal and immune niches between single and colonized DTCs in a single pore microenvironment.
Fig. 7: Multiplex IHS imaging-based characterization of heterogeneity in overt metastatic microenvironments.
Fig. 8: Proposed microenvironmental regulation of DTCs.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information.

References

  1. 1.

    Luzzi, K. J. et al. Multistep nature of metastatic inefficiency—dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153, 865–873 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  PubMed  Google Scholar 

  3. 3.

    Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    Google Scholar 

  5. 5.

    Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

    CAS  Google Scholar 

  6. 6.

    Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    He, F. et al. Multiscale characterization of the mineral phase at skeletal sites of breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 10542–10547 (2017).

    CAS  PubMed  Google Scholar 

  8. 8.

    Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).

    Google Scholar 

  9. 9.

    Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).

    CAS  PubMed  Google Scholar 

  12. 12.

    Wong, C. C. et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

    CAS  PubMed  Google Scholar 

  13. 13.

    Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867–874 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Barkan, D. et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 70, 5706–5716 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).

    CAS  PubMed  Google Scholar 

  19. 19.

    Muller-Hermelink, N. et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008).

    PubMed  Google Scholar 

  20. 20.

    Hanna, R. N. et al. Patrolling monocytes control tumor metastasis to the lung. Science 350, 985–990 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kang, Y. & Pantel, K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573–581 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Francia, G., Cruz-Munoz, W., Man, S., Xu, P. & Kerbel, R. S. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat. Rev. Cancer 11, 135–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bos, P. D., Nguyen, D. X. & Massague, J. Modeling metastasis in the mouse. Curr. Opin. Pharmacol. 10, 571–577 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Shultz, L. D., Ishikawa, F. & Greiner, D. L. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 7, 118–130 (2007).

    CAS  PubMed  Google Scholar 

  26. 26.

    Bersani, F. et al. Bioengineered implantable scaffolds as a tool to study stromal-derived factors in metastatic cancer models. Cancer Res. 74, 7229–7238 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Villasante, A. & Vunjak-Novakovic, G. Tissue-engineered models of human tumors for cancer research. Expert Opin. Drug Discov. 10, 257–268 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hutmacher, D. W. et al. Can tissue engineering concepts advance tumor biology research? Trends Biotechnol. 28, 125–133 (2010).

    CAS  PubMed  Google Scholar 

  29. 29.

    Lee, J., Cuddihy, M. J. & Kotov, N. A. Three-dimensional cell culture matrices: state of the art. Tissue Eng. Part B Rev. 14, 61–86 (2008).

    CAS  PubMed  Google Scholar 

  30. 30.

    Seib, F. P., Berry, J. E., Shiozawa, Y., Taichman, R. S. & Kaplan, D. L. Tissue engineering a surrogate niche for metastatic cancer cells. Biomaterials 51, 313–319 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Stiers, P.-J., van Gastel, N., Moermans, K., Stockmans, I. & Carmeliet, G. An ectopic imaging window for intravital imaging of engineered bone tissue. JBMR Plus 2, 92–102 (2018).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Holzapfel, B. M. et al. Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone. Biomaterials 35, 4108–4115 (2014).

    CAS  PubMed  Google Scholar 

  33. 33.

    Moreau, J. E. et al. Tissue-engineered bone serves as a target for metastasis of human breast cancer in a mouse model. Cancer Res. 67, 10304–10308 (2007).

    CAS  PubMed  Google Scholar 

  34. 34.

    Schuster, J., Zhang, J. & Longo, M. A novel human osteoblast-derived severe combined immunodeficiency mouse model of bone metastasis. J. Neurosurg. Spine 4, 388–391 (2006).

    PubMed  Google Scholar 

  35. 35.

    Thibaudeau, L. et al. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone. Dis. Models Mech. 7, 299–309 (2014).

    CAS  Google Scholar 

  36. 36.

    Reinisch, A. et al. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells. Nat. Med. 22, 812–821 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lee, J. et al. Implantable microenvironments to attract hematopoietic stem/cancer cells. Proc. Natl Acad. Sci. USA 109, 19638–19643 (2012).

    CAS  PubMed  Google Scholar 

  38. 38.

    Ko, C. Y. et al. The use of chemokine-releasing tissue engineering scaffolds in a model of inflammatory response-mediated melanoma cancer metastasis. Biomaterials 33, 876–885 (2012).

    CAS  PubMed  Google Scholar 

  39. 39.

    Aguado, B. A. et al. Secretome identification of immune cell factors mediating metastatic cell homing. Sci. Rep. 5, 17566 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Vaiselbuh, S. R., Edelman, M., Lipton, J. M. & Liu, J. M. Ectopic human mesenchymal stem cell-coated scaffolds in NOD/SCID mice: an in vivo model of the leukemia niche. Tissue Eng. Part C Methods 16, 1523–1531 (2010).

    CAS  PubMed  Google Scholar 

  41. 41.

    Aguado, B. A., Bushnell, G. G., Rao, S. S., Jeruss, J. S. & Shea, L. D. Engineering the pre-metastatic niche. Nat. Biomed. Eng. 1, 0077 (2017).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Azarin, S. M. et al. In vivo capture and label-free detection of early metastatic cells. Nat. Commun. 6, 8094 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Rao, S. S. et al. Enhanced survival with implantable scaffolds that capture metastatic breast cancer cells in bivo. Cancer Res. 76, 5209–5218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  PubMed  Google Scholar 

  45. 45.

    Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Inoue, M. et al. Graft-versus-tumor effect in a patient with advanced neuroblastoma who received HLA haplo-identical bone marrow transplantation. Bone Marrow Transplant. 32, 103–106 (2003).

    CAS  PubMed  Google Scholar 

  47. 47.

    Lee, J., Shanbhag, S. & Kotov, N. A. Inverted colloidal crystals as three-dimensional microenvironments for cellular co-cultures. J. Mater. Chem. 16, 3558 (2006).

    CAS  Google Scholar 

  48. 48.

    Bryers, J. D., Giachelli, C. M. & Ratner, B. D. Engineering biomaterials to integrate and heal: the biocompatibility paradigm shifts. Biotechnol. Bioeng. 109, 1898–1911 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Stachowiak, A. N., Bershteyn, A., Tzatzalos, E. & Irvine, D. J. Bioactive hydrogels with an ordered cellular structure combine interconnected macroporosity and robust mechanical properties. Adv. Mater. 17, 399–403 (2005).

    CAS  Google Scholar 

  50. 50.

    Kotov, N. A. et al. Inverted colloidal crystals as three-dimensional cell scaffolds. Langmuir 20, 7887–7892 (2004).

    CAS  PubMed  Google Scholar 

  51. 51.

    Joao, C. F., Vasconcelos, J. M., Silva, J. C. & Borges, J. P. An overview of inverted colloidal crystal systems for tissue engineering. Tissue Eng. Part B Rev. 20, 437–454 (2014).

    CAS  PubMed  Google Scholar 

  52. 52.

    Parekkadan, B. & Milwid, J. M. Mesenchymal stem cells as therapeutics. Annu. Rev. Biomed. Eng. 12, 87–117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Rutkowski, M. R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    CAS  PubMed  Google Scholar 

  54. 54.

    Li, A., Dubey, S., Varney, M. L., Dave, B. J. & Singh, R. K. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 170, 3369–3376 (2003).

    CAS  PubMed  Google Scholar 

  55. 55.

    Lee, E. et al. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat. Commun. 5, 4715 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Havens, A. M. et al. An in vivo mouse model for human prostate cancer metastasis. Neoplasia 10, 371–380 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

    PubMed  Google Scholar 

  58. 58.

    Tai, S. et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate 71, 1668–1679 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Kitamura, T., Qian, B. Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Nakahara, T., Norberg, S. M., Shalinsky, D. R., Hu-Lowe, D. D. & McDonald, D. M. Effect of inhibition of vascular endothelial growth factor signaling on distribution of extravasated antibodies in tumors. Cancer Res. 66, 1434–1445 (2006).

    CAS  PubMed  Google Scholar 

  61. 61.

    Levine, J. E. Implications of TNF-alpha in the pathogenesis and management of GVHD. Int. J. Hematol. 93, 571–577 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zeiser, R. & Blazar, B. R. Acute graft-versus-host disease—biologic process, prevention, and therapy. N. Engl. J. Med. 377, 2167–2179 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chung, K. et al. Structural and molecular interrogation of intact biological systems. Nature 497, 332–337 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    CAS  PubMed  Google Scholar 

  65. 65.

    McFarlane, S. et al. CD44 increases the efficiency of distant metastasis of breast cancer. Oncotarget 6, 11465–11476 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Taichman, R. S. et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE 8, e61873 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Kobayashi, A. et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 209, 639–639 (2012).

    CAS  PubMed Central  Google Scholar 

  68. 68.

    Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Bragado, P. et al. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat. Cell Biol. 15, 1351–1361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Sosa, M. S. et al. NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes. Nat. Commun. 6, 6170 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Aguirre-Ghiso, J. A., Estrada, Y., Liu, D. & Ossowski, L. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res. 63, 1684–1695 (2003).

    CAS  PubMed  Google Scholar 

  72. 72.

    Yumoto, K. et al. Axl is required for TGF-beta2-induced dormancy of prostate cancer cells in the bone marrow. Sci. Rep. 6, 36520 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Ruppender, N. et al. Cellular adhesion promotes prostate cancer cells escape from dormancy. PLoS ONE 10, e0130565 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Novak, M. L. & Koh, T. J. Phenotypic transitions of macrophages orchestrate tissue repair. Am. J. Pathol. 183, 1352–1363 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    McCracken, J. M. & Allen, L. A. Regulation of human neutrophil apoptosis and lifespan in health and disease. J. Cell Death 7, 15–23 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).

    CAS  Google Scholar 

  77. 77.

    Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).

    CAS  PubMed  Google Scholar 

  78. 78.

    Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    CAS  PubMed  Google Scholar 

  79. 79.

    Jacob, L., Kostev, K., Rathmann, W. & Kalder, M. Impact of metformin on metastases in patients with breast cancer and type 2 diabetes. J. Diabetes Complications 30, 1056–1059 (2016).

    PubMed  Google Scholar 

  80. 80.

    Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10, 2298–2308 (2011).

    CAS  PubMed  Google Scholar 

  81. 81.

    Dondossola, E. et al. Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng. 1, 0007 (2016).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Nair, A. & Tang, L. Influence of scaffold design on host immune and stem cell responses. Semin. Immunol. 29, 62–71 (2017).

    CAS  PubMed  Google Scholar 

  83. 83.

    Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Bencherif, S. A. et al. Injectable cryogel-based whole-cell cancer vaccines. Nat. Commun. 6, 7556 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Sadtler, K. et al. Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science 352, 366–370 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Swartzlander, M. D. et al. Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. Biomaterials 41, 79–88 (2015).

    CAS  PubMed  Google Scholar 

  88. 88.

    Lee, J., Heckl, D. & Parekkadan, B. Multiple genetically engineered humanized microenvironments in a single mouse. Biomater. Res. 20, 19 (2016).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Tentler, J. J. et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    White, L., Meyer, P. R. & Benedict, W. F. Establishment and characterization of a human T-cell leukemia line (LALW-2) in nude mice. J. Natl Cancer Inst. 72, 1029–1038 (1984).

    CAS  PubMed  Google Scholar 

  91. 91.

    Baron, F. et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J. Clin. Oncol. 23, 1993–2003 (2005).

    PubMed  Google Scholar 

  92. 92.

    Korngold, R., Marini, J. C., de Baca, M. E., Murphy, G. F. & Giles-Komar, J. Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responses. Biol. Blood Marrow Transplant. 9, 292–303 (2003).

    CAS  PubMed  Google Scholar 

  93. 93.

    Roth, M. D. & Harui, A. Human tumor infiltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model. J. Immunother. Cancer 3, 12 (2015).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Simpson-Abelson, M. R. et al. Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2R null mice. J. Immunol. 180, 7009–7018 (2008).

    CAS  PubMed  Google Scholar 

  95. 95.

    El Rayes, T. et al. Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1. Proc. Natl Acad. Sci. USA 112, 16000–16005 (2015).

    CAS  PubMed  Google Scholar 

  96. 96.

    De Cock, J. M. et al. Inflammation triggers Zeb1-dependent escape from tumor latency. Cancer Res. 76, 6778–6784 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl Med. 8, 361ra138 (2016).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017).

    PubMed  Google Scholar 

  100. 100.

    Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Sainson, R. C. et al. TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood 111, 4997–5007 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176–1190 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    CAS  PubMed  Google Scholar 

  104. 104.

    Jespersen, H. et al. Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model. Nat. Commun. 8, 707 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Marin Navarro, A., Susanto, E., Falk, A. & Wilhelm, M. Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies. Cell Death Discov. 4, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Patel, A. A. et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J. Exp. Med. 214, 1913–1923 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Drake, A. C., Chen, Q. & Chen, J. Engineering humanized mice for improved hematopoietic reconstitution. Cell. Mol. Immunol. 9, 215–224 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Powell, D. R. & Huttenlocher, A. Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52 (2016).

    CAS  PubMed  Google Scholar 

  109. 109.

    Reichman, H., Karo-Atar, D. & Munitz, A. Emerging roles for eosinophils in the tumor microenvironment. Trends Cancer 2, 664–675 (2016).

    PubMed  Google Scholar 

  110. 110.

    Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Green, J. J. & Elisseeff, J. H. Mimicking biological functionality with polymers for biomedical applications. Nature 540, 386–394 (2016).

    CAS  PubMed  Google Scholar 

  112. 112.

    Aguado, B. A. et al. Biomaterial scaffolds as pre-metastatic niche mimics systemically alter the primary tumor and tumor microenvironment. Adv. Healthc. Mater. 7, e1700903 (2018).

    PubMed  Google Scholar 

  113. 113.

    MacKie, R. M., Reid, R. & Junor, B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N. Engl. J. Med. 348, 567–568 (2003).

    PubMed  Google Scholar 

  114. 114.

    Strauss, D. C. & Thomas, J. M. Transmission of donor melanoma by organ transplantation. Lancet Oncol. 11, 790–796 (2010).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank the University of Massachusetts Amherst Animal Care Services, A. Burnside for assistance with animal imaging and flow cytometry, and J. Bergan for assistance with tissue clearing and imaging analyses. We also thank J. Chambers and the University of Massachusetts Amherst Light Microscope Facility and Nikon Center of Excellence for assistance with Nikon software and workstations, and L. Minter for discussing human immune cell activity in NSG mice. R.A.C. was supported by a National Science Foundation Research Traineeship (1545399). This work was supported by the National Cancer Institute (R00 CA163671) and the Institute for Applied Life Sciences to J.L.

Author information

Affiliations

Authors

Contributions

R.A.C. and J.L. designed and performed the experiments, analysed and interpreted the results, and wrote the manuscript. J.K. assisted with experiments, conducted image processing and analyses, and participated in the writing of the manuscript. S.R.P. designed the experiments, interpreted the results and wrote the manuscript.

Corresponding author

Correspondence to Jungwoo Lee.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary Information

Supplementary Information

Supplementary Methods 1–3, Supplementary Figures 1–21, Supplementary Table 1 and Supplementary Video Caption 1.

Reporting Summary

Supplementary Video 1

Tissue-cleared scaffold with blood-vessel and tumour staining.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Carpenter, R.A., Kwak, JG., Peyton, S.R. et al. Implantable pre-metastatic niches for the study of the microenvironmental regulation of disseminated human tumour cells. Nat Biomed Eng 2, 915–929 (2018). https://doi.org/10.1038/s41551-018-0307-x

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing