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From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

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Abstract

The extracellular matrix (ECM) is a guiding force that regulates various developmental stages of the breast. In addition to providing structural support for the cells, it mediates epithelial-stromal communication and provides cues for cell survival, proliferation, and differentiation. Perturbations in ECM architecture profoundly influence breast tumor progression and metastasis. Understanding how a dysregulated ECM can facilitate malignant transformation is crucial to designing treatments to effectively target the tumor microenvironment. Here, we address the contribution of ECM mechanics to breast cancer progression, metastasis, and treatment resistance and discuss potential therapeutic strategies targeting the ECM.

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References

  1. Wiseman, B. S., & Werb, Z. (2002). Stromal effects on mammary gland development and breast cancer. Science (New York, N.Y.), 296(5570), 1046–1049. doi:10.1126/science.1067431.

    Article  CAS  Google Scholar 

  2. Robinson, G. W., Karpf, a. B., & Kratochwil, K. (1999). Regulation of mammary gland development by tissue interaction. Journal of Mammary Gland Biology and Neoplasia, 4(1), 9–19. doi:10.1023/A:1018748418447.

    Article  CAS  PubMed  Google Scholar 

  3. Wicha, M. S., Liotta, L. A., Vonderhaar, B. K., & Kidwell, W. R. (1980). Effects of inhibition of basement membrane collagen deposition on rat mammary gland development. Developmental Biology, 80(2), 253–266. doi:10.1016/0012-1606(80)90402-9.

    Article  CAS  PubMed  Google Scholar 

  4. Silberstein, G. B., & Daniel, C. W. (1982). Glycosaminoglycans in the basal lamina and extracellular matrix of the developing mouse mammary duct. Developmental Biology, 90(1), 215–222. doi:10.1016/0012-1606(82)90228-7.

    Article  CAS  PubMed  Google Scholar 

  5. Fata, J. E., Werb, Z., & Bissell, M. J. (2004). Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast cancer research: BCR, 6(1), 1–11. doi:10.1186/bcr634.

    CAS  PubMed  Google Scholar 

  6. Paszek, M. J., & Weaver, V. M. (2004). The tension mounts: mechanics meets morphogenesis and malignancy. Journal of Mammary Gland Biology and Neoplasia. doi:10.1007/s10911-004-1404-x.

    PubMed  Google Scholar 

  7. Schedin, P., & Keely, P. J. (2011). Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harbor Perspectives in Biology, 3(1), 1–22. doi:10.1101/cshperspect.a003228.

    Article  CAS  Google Scholar 

  8. Schedin, P., & Keely, P. J. (2011). and Mechanosignaling in normal development and tumor progression, 1–22. doi:10.1101/cshperspect.a003228.

  9. Schedin, P., Mitrenga, T., McDaniel, S., & Kaeck, M. (2004). Mammary ECM composition and function are altered by reproductive state. Molecular Carcinogenesis, 41(4), 207–220. doi:10.1002/mc.20058.

    Article  CAS  PubMed  Google Scholar 

  10. Hynes, R. O. (2009). The extracellular matrix: not just pretty fibrils. Science (New York, N.Y.), 326(5957), 1216–1219. doi:10.1126/science.1176009.

    Article  CAS  Google Scholar 

  11. Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer TL - 15. EMBO Reports, 15 VN-r(12). doi:10.15252/embr.201439246.

  12. Sweet, D. T., Chen, Z., Wiley, D. M., Bautch, V. L., & Tzima, E. (2012). The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis. Blood, 119(8), 1946–1955. doi:10.1182/blood-2011-10-384560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Newman, a. C., Nakatsu, M. N., Chou, W., Gershon, P. D., & Hughes, C. C. W. (2011). The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Molecular Biology of the Cell, 22(20), 3791–3800. doi:10.1091/mbc.E11-05-0393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Myers, K. A., Applegate, K. T., Danuser, G., Fischer, R. S., & Waterman, C. M. (2011). Distinct ECM mechanosensing pathways regulate microtubule dynamics to control endothelial cell branching morphogenesis. Journal of Cell Biology, 192(2), 321–334. doi:10.1083/jcb.201006009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sorokin, L. (2010). The impact of the extracellular matrix on inflammation. Nature reviews. Immunology, 10(10), 712–723. doi:10.1038/nri2852.

    CAS  PubMed  Google Scholar 

  16. Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: a dynamic niche in cancer progression. Journal of Cell Biology, 196(4), 395–406. doi:10.1083/jcb.201102147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Egeblad, M., Rasch, M. G., & Weaver, V. M. (2010). Dynamic interplay between the collagen scaffold and tumor evolution. Current Opinion in Cell Biology. doi:10.1016/j.ceb.2010.08.015.

    PubMed  PubMed Central  Google Scholar 

  18. Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine, 4(1), 38. doi:10.1186/1741-7015-4-38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Huijbers, I. J., Iravani, M., Popov, S., Robertson, D., Al-Sarraj, S., Jones, C., & Isacke, C. M. (2010). A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PloS One, 5(3). doi:10.1371/journal.pone.0009808.

  20. Zhu, G. G., Risteli, L., Makinen, M., Risteli, J., Kauppila, A., & Stenback, F. (1995). Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer, 75(4), 1010–1017. doi:10.1002/1097-0142(19950215)75:4<1010::AID-CNCR2820750417>3.0.CO;2-O.

    Article  CAS  PubMed  Google Scholar 

  21. Kauppila, S., Stenbäck, F., Risteli, J., Jukkola, A., & Risteli, L. (1998). Aberrant type I and type III collagen gene expression in human breast cancer in vivo. The Journal of Pathology, 186(3), 262–268. doi:10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  22. Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., … Weaver, V. M. (2005). Tensional homeostasis and the malignant phenotype. Cancer cell, 8(3), 241–54. doi: 10.1016/j.ccr.2005.08.010

  23. Lu, P., Takai, K., Weaver, V. M., & Werb, Z. (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspectives in Biology, 3(12), 1–24. doi:10.1101/cshperspect.a005058.

    Article  Google Scholar 

  24. Lopez, J. I., Kang, I., You, W.-K., McDonald, D. M., & Weaver, V. M. (2011). In situ force mapping of mammary gland transformation. Integrative biology: quantitative biosciences from nano to macro, 3(9), 910–921. doi:10.1039/c1ib00043h.

    Article  CAS  Google Scholar 

  25. Hu, M., Yao, J., Carroll, D. K., Weremowicz, S., Chen, H., Carrasco, D., … Polyak, K. (2008). Regulation of in situ to invasive breast carcinoma transition. Cancer Cell, 13(5), 394–406. doi: 10.1016/j.ccr.2008.03.007

  26. Lerwill, M. F. (2004). Current practical applications of diagnostic immunohistochemistry in breast pathology. The American Journal of Surgical Pathology, 28, 1076–1091. doi:10.1097/01.pas.0000126780.10029.f0.

    Article  PubMed  Google Scholar 

  27. Ursin, G., Hovanessian-Larsen, L., Parisky, Y. R., Pike, M. C., & Wu, A. H. (2005). Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Research, 7(5), R605–R608. doi:10.1186/bcr1260.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Acerbi, I., Cassereau, L., Dean, I., Shi, Q., Au, A., Park, C., … Weaver, V. M. (2015). Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integrative biology: quantitative biosciences from nano to macro, 7(10), 1120–34. doi: 10.1039/c5ib00040h

  29. Conklin, M. W., Eickhoff, J. C., Riching, K. M., Pehlke, C. A., Eliceiri, K. W., Provenzano, P. P., … Keely, P. J. (2011). Aligned collagen is a prognostic signature for survival in human breast carcinoma. American Journal of Pathology, 178(3), 1221–1232. doi: 10.1016/j.ajpath.2010.11.076

  30. Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Erler, J. T., Fong, S. F. T., … Weaver, V. M. (2010). NIH Public Access, 139(5), 891–906. doi: 10.1016/j.cell.2009.10.027.Matrix

  31. Ding, J., Warren, R., Girling, A., Thompson, D., & Easton, D. (n.d.). Mammographic density, estrogen receptor status and other breast cancer tumor characteristics. The Breast Journal, 16(3), 279–289. doi:10.1111/j.1524-4741.2010.00907.x.

  32. Conroy, S. M., Butler, L. M., Harvey, D., Gold, E. B., Sternfeld, B., Greendale, G. A., & Habel, L. A. (2011). Metabolic syndrome and mammographic density: the Study of Women’s Health Across the Nation. International Journal of Cancer, 129(7), 1699–1707. doi:10.1002/ijc.25790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yaghjyan, L., Colditz, G. A., Collins, L. C., Schnitt, S. J., Rosner, B., Vachon, C., & Tamimi, R. M. (2011). Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. Journal of the National Cancer Institute, 103(15), 1179–1189. doi:10.1093/jnci/djr225.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hugh, J., Hanson, J., Cheang, M. C. U., Nielsen, T. O., Perou, C. M., Dumontet, C., … Vogel, C. (2009). Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 27(8), 1168–76. doi: 10.1200/JCO.2008.18.1024

  35. Chang, R.-F., Chen, H.-H., Chang, Y.-C., Huang, C.-S., Chen, J.-H., & Lo, C.-M. (2016). Quantification of breast tumor heterogeneity for ER status, HER2 status, and TN molecular subtype evaluation on DCE-MRI. Magnetic Resonance Imaging, 34(6), 809–819. doi:10.1016/j.mri.2016.03.001.

    Article  CAS  PubMed  Google Scholar 

  36. Park, S. Y., Kim, H. M., & Koo, J. S. (2015). Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Research and Treatment, 149(3), 727–741. doi:10.1007/s10549-015-3291-9.

    Article  CAS  PubMed  Google Scholar 

  37. Afik, R., Zigmond, E., Vugman, M., Klepfish, M., Shimshoni, E., Pasmanik-Chor, M., … Varol, C. (2016). Tumor macrophages are pivotal constructors of tumor collagenous matrix. Journal of Experimental Medicine.

  38. Tchou, J., Kossenkov, A. V, Chang, L., Satija, C., Herlyn, M., Showe, L. C., … Gelmon, K. (2012). Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Medical Genomics, 5(1), 39. doi: 10.1186/1755-8794-5-39

  39. Galbraith, C. G., Yamada, K. M., & Sheetz, M. P. (2002). The relationship between force and focal complex development. Journal of Cell Biology, 159(4), 695–705. doi:10.1083/jcb.200204153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. White, D. E., Kurpios, N. A., Zuo, D., Hassell, J. A., Blaess, S., Mueller, U., & Muller, W. J. (2004). Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell, 6(2), 159–170. doi:10.1016/j.ccr.2004.06.025\rS1535610804002077 [pii].

    Article  CAS  PubMed  Google Scholar 

  41. Wozniak, M. a., Desai, R., Solski, P. a., Der, C. J., & Keely, P. J. (2003). ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. The Journal of Cell Biology, 163(3), 583–595. doi:10.1083/jcb.200305010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., & Keely, P. J. (2009). Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene, 28(49), 4326–4343. doi:10.1038/onc.2009.299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rubashkin, M. G., Cassereau, L., Bainer, R., DuFort, C. C., Yui, Y., Ou, G., … Weaver, V. M. (2014). Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Research, 74(17), 4597–4611. doi: 10.1158/0008-5472.CAN-13-3698

  44. Mouw, J. K., Yui, Y., Damiano, L., Bainer, R. O., Lakins, J. N., Acerbi, I., … Weaver, V. M. (2014). Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nature medicine, 20(4), 360–7. doi: 10.1038/nm.3497

  45. Gehler, S., Ponik, S. M., Riching, K. M., & Keely, P. J. (2013). Bi-directional signaling: extracellular matrix and integrin regulation of breast tumor progression. Critical Reviews in Eukaryotic Gene Expression, 23(2), 139–157. doi:10.1615/CritRevEukarGeneExpr.2013006647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhu, J., Xiong, G., Trinkle, C., & Xu, R. (2014). Integrated extracellular matrix signaling in mammary gland development and breast cancer progression. Histology and Histopathology, 29(9), 1083–1092. doi:10.1002/jcp.24872.The.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Franco, C., Hou, G., Ahmad, P. J., Fu, E. Y. K., Koh, L., Vogel, W. F., & Bendeck, M. P. (2008). Discoidin domain receptor 1 (Ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice. Circulation Research, 102(10), 1202–1211. doi:10.1161/CIRCRESAHA.107.170662.

    Article  CAS  PubMed  Google Scholar 

  48. Meyaard, L. (2008). The inhibitory collagen receptor LAIR-1 (CD305). Journal of Leukocyte Biology, 83(4), 799–803. doi:10.1189/jlb.0907609.

    Article  CAS  PubMed  Google Scholar 

  49. Houghton, A. M., Quintero, P. A., Perkins, D. L., Kobayashi, D. K., Kelley, D. G., Marconcini, L. A., … Shapiro, S. D. (2006). Elastin fragments drive disease progression in a murine model of emphysema. Journal of Clinical Investigation, 116(3), 753–759. doi: 10.1172/JCI25617

  50. Krishnan, R., & Cleary, E. G. (1990). Elastin gene expression in elastotic human breast cancers and epithelial cell lines. Cancer Research, 50(7), 2164–2171.

    CAS  PubMed  Google Scholar 

  51. García-Mendoza, M. G., Inman, D. R., Ponik, S. M., Jeffery, J. J., Sheerar, D. S., Van Doorn, R. R., & Keely, P. J. (2016). Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironment. Breast cancer research: BCR, 18(1), 49. doi:10.1186/s13058-016-0703-7.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860–867. doi:10.1038/nature01322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sieminski, A. L., Hebbel, R. P., & Gooch, K. J. (2004). The relative magnitudes of endothelial force generation and matrix stiffness modulate capillary morphogenesis in vitro. Experimental Cell Research, 297(2), 574–584. doi:10.1016/j.yexcr.2004.03.035.

    Article  CAS  PubMed  Google Scholar 

  54. Teo, N. B., Shoker, B. S., Jarvis, C., Martin, L., Sloane, J. P., & Holcombe, C. (2002). Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast. British Journal of Cancer, 86(6), 905–911. doi:10.1038/sj.bjc.6600053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mason, B. N., Starchenko, A., Williams, R. M., Bonassar, L. J., & Reinhart-King, C. A. (2013). Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. Acta Biomaterialia, 9(1), 4635–4644. doi:10.1016/j.actbio.2012.08.007.

    Article  CAS  PubMed  Google Scholar 

  56. Kohn, J. C., Zhou, D. W., Bordeleau, F., Zhou, A. L., Mason, B. N., Mitchell, M. J., … Reinhart-King, C. A. (2015). Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. Biophysical Journal, 108(3), 471–478. doi: 10.1016/j.bpj.2014.12.023

  57. Kaplan, R. N., Rafii, S., & Lyden, D. (2006). Preparing the “soil”: the premetastatic niche. Cancer Research. doi:10.1158/0008-5472.CAN-06-2407.

    PubMed Central  Google Scholar 

  58. Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature reviews. Cancer, 2(8), 563–572. doi:10.1038/nrc865.

    CAS  PubMed  Google Scholar 

  59. Nguyen, D. X., Bos, P. D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature reviews. Cancer, 9(4), 274–284. doi:10.1038/nrc2622.

    CAS  PubMed  Google Scholar 

  60. Cox, T. R., Rumney, R. M., Schoof, E. M., Perryman, L., Hoye, A. M., Agrawal, A., … Erler, J. T. (2015). The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature, 522(7554), 106–110. doi: 10.1038/nature14492

  61. Miller, B. W., Morton, J. P., Pinese, M., Saturno, G., Jamieson, N. B., McGhee, E., … Sansom, O. J. (2015). Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med, 7, 1063–1076. doi: 10.15252/emmm

  62. Erler, J. T., & Weaver, V. M. (2009). Three-dimensional context regulation of metastasis. Clinical and Experimental Metastasis, 26(1), 35–49. doi:10.1007/s10585-008-9209-8.

    Article  PubMed  Google Scholar 

  63. Giles, A. J., Reid, C. M., De Wayne Evans, J., Murgai, M., Vicioso, Y., Highfill, S. L., … Kaplan, R. N. (2016). Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Research, 76(6), 1335–1347. doi: 10.1158/0008-5472.CAN-15-0204

  64. Gao, D., Joshi, N., Choi, H., Ryu, S., Hahn, M., Catena, R., … Mittal, V. (2012). Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research, 72(6), 1384–1394. doi: 10.1158/0008-5472.CAN-11-2905

  65. Kagan, H. M., & Li, W. (2003). Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. Journal of Cellular Biochemistry, 88(4), 660–672. doi:10.1002/jcb.10413.

    Article  CAS  PubMed  Google Scholar 

  66. Pfeiffer, B. J., Franklin, C. L., Hsieh, F. H., Bank, R. A., & Phillips, C. L. (2005). Alpha 2(I) collagen deficient oim mice have altered biomechanical integrity, collagen content, and collagen crosslinking of their thoracic aorta. Matrix Biology, 24(7), 451–458. doi:10.1016/j.matbio.2005.07.001.

    Article  CAS  PubMed  Google Scholar 

  67. Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., … Giaccia, A. J. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1), 35–44. doi: 10.1016/j.ccr.2008.11.012

  68. Kaplan, R. N., Riba, R. D., Zacharoulis, S., Anna, H., Vincent, L., Costa, C., … Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827. doi: 10.1038/nature04186.VEGFR1-positive

  69. Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., … Giaccia, A. J. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–6. doi: 10.1038/nature04695

  70. Wong, C. C.-L., Gilkes, D. M., Zhang, H., Chen, J., Wei, H., Chaturvedi, P., … Semenza, G. L. (2011). Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proceedings of the National Academy of Sciences of the United States of America, 108(39), 16369–74. doi: 10.1073/pnas.1113483108

  71. Fogelgren, B., Polgár, N., Szauter, K. M., Újfaludi, Z., Laczkó, R., Fong, K. S. K., & Csiszar, K. (2005). Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. Journal of Biological Chemistry, 280(26), 24690–24697. doi:10.1074/jbc.M412979200.

    Article  CAS  PubMed  Google Scholar 

  72. Høye, A. M., & Erler, J. T. (2016). Structural ECM components in the pre-metastatic and metastatic niche. American Journal of Physiology. Cell Physiology, 1(73) ajpcell.00326.2015. doi:10.1152/ajpcell.00326.2015.

  73. Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., … Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329–35. doi: 10.1038/nature15756

  74. Hsemann, Y., Geigl, J. B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., … Klein, C. A. (2008). Systemic spread is an early step in breast cancer. Cancer Cell, 13(1), 58–68. doi: 10.1016/j.ccr.2007.12.003

  75. Kennecke, H., Yerushalmi, R., Woods, R., Cheang, M. C. U., Voduc, D., Speers, C. H., … Gelmon, K. (2010). Metastatic behavior of breast cancer subtypes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 28(20), 3271–7. doi: 10.1200/JCO.2009.25.9820

  76. Rizwan, A., Bulte, C., Kalaichelvan, A., Cheng, M., Krishnamachary, B., Bhujwalla, Z. M., … Tyers, M. (2015). Metastatic breast cancer cells in lymph nodes increase nodal collagen density. Scientific Reports, 5, 10002. doi: 10.1038/srep10002

  77. Koyama, T., Hasebe, T., Tsuda, H., Hirohashi, S., Sasaki, S., Fukutomi, T., … Mukai, K. (1999). Histological factors associated with initial bone metastasis of invasive ductal carcinoma of the breast. Japanese Journal of Cancer Research, 90(3), 294–300. doi: 10.1111/j.1349-7006.1999.tb00747.x

  78. Lawson, D. A., Bhakta, N. R., Kessenbrock, K., Prummel, K. D., Yu, Y., Takai, K., … Werb, Z. (2015). Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature, 526(7571), 131–135. doi: 10.1038/nature15260

  79. Oskarsson, T., Acharyya, S., Zhang, X. H.-F., Vanharanta, S., Tavazoie, S. F., Morris, P. G., … Massagué, J. (2011). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature medicine, 17(7), 867–74. doi: 10.1038/nm.2379

  80. O’Connell, J. T., Sugimoto, H., Cooke, V. G., MacDonald, B. A., Mehta, A. I., LeBleu, V. S., … Kalluri, R. (2011). VEGF-A and tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proceedings of the National Academy of Sciences of the United States of America, 108(38), 16002–7. doi: 10.1073/pnas.1109493108

  81. Malanchi, I., Santamaria-Martínez, A., Susanto, E., Peng, H., Lehr, H.-A., Delaloye, J.-F., & Huelsken, J. (2011). Interactions between cancer stem cells and their niche govern metastatic colonization. Nature, 481(7379), 85–89. doi:10.1038/nature10694.

    Article  PubMed  Google Scholar 

  82. Aguirre-Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K., & Ossowski, L. (2001). Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Molecular Biology of the Cell, 12(4), 863–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Barkan, D., Green, J. E., & Chambers, A. F. (2010). Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. European Journal of Cancer, 46(7), 1181–1188. doi:10.1016/j.ejca.2010.02.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hayashi, M., Yamamoto, Y., Ibusuki, M., Fujiwara, S., Yamamoto, S., Tomita, S., … Iwase, H. (2012). Evaluation of tumor stiffness by elastography is predictive for pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer. Annals of Surgical Oncology, 19(9), 3042–3049. doi: 10.1245/s10434-012-2343-1

  85. Giussani, M., Merlino, G., Cappelletti, V., Tagliabue, E., & Daidone, M. G. (2015). Tumor-extracellular matrix interactions: identification of tools associated with breast cancer progression. Seminars in Cancer Biology. doi:10.1016/j.semcancer.2015.09.012.

    PubMed  Google Scholar 

  86. Magzoub, M., Jin, S., & Verkman, a. S. (2008). Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 22(1), 276–284. doi:10.1096/fj.07-9150com.

    Article  CAS  Google Scholar 

  87. Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J., & Jain, R. K. (2000). Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Research, 60(9), 2497–2503. doi:10.1126/science.271.5252.1079.

    CAS  PubMed  Google Scholar 

  88. Erikson, A., Andersen, H. N., Naess, S. N., Sikorski, P., & Davies, C. D. L. (2008). Physical and chemical modifications of collagen gels: impact on diffusion. Biopolymers, 89(2), 135–143. doi:10.1002/bip.20874.

    Article  CAS  PubMed  Google Scholar 

  89. Farmer, P., Bonnefoi, H., Anderle, P., Cameron, D., Wirapati, P., Becette, V., … Delorenzi, M. (2009). A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nature medicine, 15(1), 68–74. doi: 10.1038/nm0209-220a

  90. Misra, S., Obeid, L. M., Hannun, Y. A., Minamisawa, S., Berger, F. G., Markwald, R. R., … Ghatak, S. (2008). Hyaluronan constitutively regulates activation of COX-2-mediated cell survival activity in intestinal epithelial and colon carcinoma cells. Journal of Biological Chemistry, 283(21), 14335–14344. doi: 10.1074/jbc.M703811200

  91. Jansen, M. P. H. M., Foekens, J. a, van Staveren, I. L., Dirkzwager-Kiel, M. M., Ritstier, K., Look, M. P., … Berns, E. M. J. J. (2005). Molecular classification of tamoxifen-resistant breast carcinomas by gene expression profiling. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 23(4), 732–40. doi: 10.1200/JCO.2005.05.145

  92. Thurber, G. M., Schmidt, M. M., & Wittrup, K. D. (2008). Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Advanced Drug Delivery Reviews. doi:10.1016/j.addr.2008.04.012.

    PubMed  PubMed Central  Google Scholar 

  93. Holle, A. W., Young, J. L., & Spatz, J. P. (2016). In vitro cancer cell-ECM interactions inform in vivo cancer treatment. Advanced Drug Delivery Reviews. doi:10.1016/j.addr.2015.10.007.

    PubMed  Google Scholar 

  94. Chrenek, M. a., Wong, P., & Weaver, V. M. (2001). Tumour-stromal interactions. Integrins and cell adhesions as modulators of mammary cell survival and transformation. Breast cancer research: BCR, 3(4), 224–229. doi:10.1186/bcr300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sloan, E. K., Pouliot, N., Stanley, K. L., Chia, J., Moseley, J. M., Hards, D. K., & Anderson, R. L. (2006). Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Research, 8(2), R20. doi:10.1186/bcr1398.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Seguin, L., Kato, S., Franovic, A., Camargo, M. F., Lesperance, J., Elliott, K. C., … Cheresh, D. A. (2014). An integrin β3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature cell biology, 16(5), 457–68. doi: 10.1038/ncb2953

  97. Barkan, D., & Chambers, A. F. (2011). B1-integrin: a potential therapeutic target in the battle against cancer recurrence. Clinical Cancer Research. doi:10.1158/1078-0432.CCR-11-0642.

    PubMed  Google Scholar 

  98. Das, S., Ongusaha, P. P., Yang, Y. S., Park, J.-M., Aaronson, S. a., & Lee, S. W. (2006). Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Research, 66, 8123–8130. doi:10.1158/0008-5472.CAN-06-1215.

    Article  CAS  PubMed  Google Scholar 

  99. Rammal, H., Saby, C., Magnien, K., Van-Gulick, L., Garnotel, R., Buache, E., … Morjani, H. (2016). Discoidin domain receptors: potential actors and targets in cancer. Frontiers in Pharmacology. doi: 10.3389/fphar.2016.00055

  100. Bertout, J. A., Patel, S. A., & Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature reviews. Cancer, 8(12), 967–975. doi:10.1038/nrc2540.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pang, M.-F., Siedlik, M. J., Han, S., Stallings-Mann, M., Radisky, D. C., & Nelson, C. M. (2016). Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells. Cancer research. doi:10.1158/0008-5472.CAN-16-0579.

    Google Scholar 

  102. Al-Ejeh, F., Smart, C. E., Morrison, B. J., Chenevix-Trench, G., López, J. A., Lakhani, S. R., … Khanna, K. K. (2011). Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. doi: 10.1093/carcin/bgr028

  103. Naumov, G. N., Townson, J. L., MacDonald, I. C., Wilson, S. M., Bramwell, V. H. C., Groom, A. C., & Chambers, A. F. (2003). Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Research and Treatment, 82(3), 199–206. doi:10.1023/B:BREA.0000004377.12288.3c.

    Article  CAS  PubMed  Google Scholar 

  104. Barkan, D., Kleinman, H., Simmons, J. L., Asmussen, H., Kamaraju, A. K., Hoenorhoff, M. J., … Green, J. E. (2008). Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Research, 68(15), 6241–6250. doi: 10.1158/0008-5472.CAN-07-6849

  105. Schrader, J., Gordon-Walker, T. T., Aucott, R. L., van Deemter, M., Quaas, A., Walsh, S., … Iredale, J. P. (2011). Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology, 53(4), 1192–1205. doi: 10.1002/hep.24108

  106. Tilghman, R. W., Blais, E. M., Cowan, C. R., Sherman, N. E., Grigera, P. R., Jeffery, E. D., … Parsons, J. T. (2012). Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis. PLoS ONE, 7(5). doi: 10.1371/journal.pone.0037231

  107. Pupa, S. M., Giuffré, S., Castiglioni, F., Bertola, L., Cantú, M., Bongarzone, I., … Tagliabue, E. (2007). Regulation of breast cancer response to chemotherapy by fibulin-1. Cancer Research, 67(9), 4271–4277. doi: 10.1158/0008-5472.CAN-06-4162

  108. Peiris-Pagès, M., Sotgia, F., & Lisanti, M. P. (2015). Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. Oncotarget, 6(13), 10728–10745. doi:10.18632/oncotarget.3828.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature reviews. Cancer, 6(5), 392–401. doi:10.1038/nrc1877.

    Article  CAS  PubMed  Google Scholar 

  110. Shen, C. J., Sharma, A., Vuong, D.-V., Erler, J. T., Pruschy, M., & Broggini-Tenzer, A. (2014). Ionizing radiation induces tumor cell lysyl oxidase secretion. BMC Cancer, 14(1), 532. doi:10.1186/1471-2407-14-532.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Liu, J., Liao, S., Diop-Frimpong, B., Chen, W., Goel, S., Naxerova, K., … Xu, L. (2012). TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proceedings of the National Academy of Sciences of the United States of America, 109(41), 16618–23. doi: 10.1073/pnas.1117610109

  112. Bondareva, A., Downey, C. M., Ayres, F., Liu, W., Boyd, S. K., Hallgrimsson, B., & Jirik, F. R. (2009). The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PloS One, 4(5), e5620. doi:10.1371/journal.pone.0005620.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Beckenlehner, K., Bannke, S., Spruss, T., Bernhardt, G., Schönenberg, H., & Schiess, W. (1992). Hyaluronidase enhances the activity of adriamycin in breast cancer models in vitro and in vivo. Journal of Cancer Research and Clinical Oncology, 118(8), 591–596.

    Article  CAS  PubMed  Google Scholar 

  114. Shuster, S., Frost, G. I., Csoka, A. B., Formby, B., & Stern, R. (2002). Hyaluronidase reduces human breast cancer xenografts in SCID mice. International Journal of Cancer, 102(2), 192–197. doi:10.1002/ijc.10668.

    Article  CAS  PubMed  Google Scholar 

  115. Pickup, M. W., Laklai, H., Acerbi, I., Owens, P., Gorska, A. E., Chytil, A., … Moses, H. L. (2013). Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Research, 73(17), 5336–5346. doi: 10.1158/0008-5472.CAN-13-0012

  116. Barry-Hamilton, V., Spangler, R., Marshall, D., McCauley, S., Rodriguez, H. M., Oyasu, M., … Smith, V. (2010). Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nature medicine, 16(9), 1009–17. doi: 10.1038/nm.2208

  117. Chan, N., Willis, A., Kornhauser, N., Ward, M. M., Lee, S. B., Nackos, E., … Vahdat, L. (2016). Influencing the tumor microenvironment: phase 2 study of copper depletion with tetrathiomolybdate in high risk breast cancer and preclinical models of lung metastases. Clinical Cancer Research.

  118. Golubovskaya, V. M., & Cance, W. G. (2007). Focal adhesion kinase and p53 signaling in cancer cells. International Review of Cytology, 263(7), 103–153. doi:10.1016/S0074-7696(07)63003-4.

    Article  CAS  PubMed  Google Scholar 

  119. Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18(5), 516–523. doi:10.1016/j.ceb.2006.08.011.

    Article  CAS  PubMed  Google Scholar 

  120. Tanjoni, I., Walsh, C., Uryu, S., Tomar, A., Nam, J.-O., Mielgo, A., … Schlaepfer, D. D. (2010). PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer biology & therapy, 9(10), 764–77.

  121. Walsh, C., Tanjoni, I., Uryu, S., Tomar, A., Nam, J.-O., Luo, H., … Schlaepfer, D. D. (2010). Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer biology & therapy, 9(10), 778–90.

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Acknowledgements

The authors apologize to all colleagues whose work could not be cited due to space limitations. The authors would like to thank Dr. Janna Mouw for her insightful review of the manuscript. This work was supported by NIH grant RO1CA192914, USMRAA (DOD) grant BC122990, U54 grant CA210184, and UO1 grant CA202241-01.

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  1. Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, CA, USA

    Shelly Kaushik, Michael W Pickup & Valerie M Weaver

  2. Department of Anatomy, UCSF, San Francisco, CA, USA

    Valerie M Weaver

  3. Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, USA

    Valerie M Weaver

  4. Department of Radiation Oncology, UCSF, San Francisco, CA, USA

    Valerie M Weaver

  5. UCSF Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, CA, USA

    Valerie M Weaver

  6. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA

    Valerie M Weaver

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  1. Shelly Kaushik
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Correspondence to Valerie M Weaver.

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Kaushik, S., Pickup, M.W. & Weaver, V.M. From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev 35, 655–667 (2016). https://doi.org/10.1007/s10555-016-9650-0

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