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Organoids as Complex In Vitro Models for Studying Radiation-Induced Cell Recruitment

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Abstract

Patients with triple negative breast cancer (TNBC) typically receive chemotherapy, surgery, and radiation therapy. Although this treatment improves prognosis for most patients, some patients continue to experience recurrence within 5 years. Preclinical studies have shown that immune cell infiltration at the irradiated site may play a significant role in tumor cell recruitment; however, little is known about the mechanisms that govern this process. This lack of knowledge highlights the need to evaluate radiation-induced cell infiltration with models that have controllable variables and maintain biological integrity. Mammary organoids are multicellular three-dimensional (3D) in vitro models, and they have been used to examine many aspects of mammary development and tumorigenesis. Organoids are also emerging as a powerful tool to investigate normal tissue radiation damage. In this review, we evaluate recent advances in mammary organoid technology, consider the advantages of using organoids to study radiation response, and discuss future directions for the applications of this technique.

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References

  1. Acerbi, I., L. Cassereau, I. Dean, Q. Shi, A. Au, C. Park, Y. Y. Chen, J. Liphardt, E. S. Hwang, and V. M. Weaver. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7:1120–1134, 2015.

    Google Scholar 

  2. Adkins, F. C., A. M. Gonzalez-Angulo, X. Lei, L. F. Hernandez-Aya, E. A. Mittendorf, J. K. Litton, J. Wagner, K. K. Hunt, W. A. Woodward, and F. Meric-Bernstam. Triple-negative breast cancer is not a contraindication for breast conservation. Ann. Surg. Oncol. 18:3164–3173, 2011.

    Google Scholar 

  3. Adra, J., D. Lundstedt, F. Killander, E. Holmberg, M. Haghanegi, E. Kjellén, P. Karlsson, and S. Alkner. Distribution of locoregional breast cancer recurrence in relation to postoperative radiation fields and biological subtypes. Int. J. Radiat. Oncol. 105:285–295, 2019.

    Google Scholar 

  4. Afghahi, A., N. Purington, S. S. Han, M. Desai, E. Pierson, M. B. Mathur, T. Seto, C. A. Thompson, J. Rigdon, M. L. Telli, S. S. Badve, C. N. Curtis, R. B. West, K. Horst, S. L. Gomez, J. M. Ford, G. W. Sledge, and A. W. Kurian. Higher absolute lymphocyte counts predict lower mortality from early-stage triple-negative breast cancer. Clin. Cancer Res. 24:2851–2858, 2018.

    Google Scholar 

  5. Ahn, G. O., and J. M. Brown. Matrix metalloproteinase-9 Is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13:193–205, 2008.

    Google Scholar 

  6. Alcaraz, J., R. Xu, H. Mori, C. M. Nelson, R. Mroue, V. A. Spencer, D. Brownfield, D. C. Radisky, C. Bustamante, and M. J. Bissell. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 27:2829–2838, 2008.

    Google Scholar 

  7. Al-Mahmood, S., J. Sapiezynski, O. B. Garbuzenko, and T. Minko. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv. Transl. Res. 8:1483–1507, 2018.

    Google Scholar 

  8. Ambroggi, M., E. M. Stroppa, P. Mordenti, C. Biasini, A. Zangrandi, E. Michieletti, E. Belloni, and L. Cavanna. Metastatic breast cancer to the gastrointestinal tract: report of five cases and review of the literature. Int. J. Breast Cancer 1–8:2012, 2012.

    Google Scholar 

  9. Andarawewa, K. L., A. C. Erickson, W. S. Chou, S. V. Costes, P. Gascard, J. D. Mott, M. J. Bissell, and M. H. Barcellos-Hoff. Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor β-induced epithelial to mesenchymal transition. Cancer Res. 67:8662–8670, 2007.

    Google Scholar 

  10. Avivar-Valderas, A., R. McEwen, A. Taheri-Ghahfarokhi, L. S. Carnevalli, E. L. Hardaker, M. Maresca, K. Hudson, E. A. Harrington, and F. Cruzalegui. Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer. Oncotarget 9:21444–21458, 2018.

    Google Scholar 

  11. Ayuso, J. M., A. Gillette, K. Lugo-Cintrón, S. Acevedo-Acevedo, I. Gomez, M. Morgan, T. Heaster, K. B. Wisinski, S. P. Palecek, M. C. Skala, and D. J. Beebe. Organotypic microfluidic breast cancer model reveals starvation-induced spatial-temporal metabolic adaptations. EBioMedicine 37:144–157, 2018.

    Google Scholar 

  12. Bagley, J. A., D. Reumann, S. Bian, J. Lévi-Strauss, and J. A. Knoblich. Fused cerebral organoids model interactions between brain regions. Nat. Methods 14:743–751, 2017.

    Google Scholar 

  13. Bakal, C., G. Church, and N. Perrimon. Regulating Cell Morphology. Science 316:1753–1756, 2007.

    Google Scholar 

  14. Baker, D. G., and R. J. Krochak. The response of the microvascular system to radiation: a review. Cancer Invest. 7:287–294, 1989.

    Google Scholar 

  15. Barcellos-Hoff, M., R. Derynck, M.-S. Tsang, and J. Weatherbee. Transforming growth factor-b activation in irradiated murine mammary gland. J. Clinc. Invest. 92:2065–2072, 1993.

    Google Scholar 

  16. Barcellos-Hoff, M. H., and S. A. Ravani. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60:1254–1260, 2000.

    Google Scholar 

  17. Barreto-Andrade, J. C., E. V. Efimova, H. J. Mauceri, M. A. Beckett, H. G. Sutton, T. E. Darga, E. E. Vokes, M. C. Posner, S. J. Kron, and R. R. Weichselbaum. response of human prostate cancer cells and tumors to combining parp inhibition with ionizing radiation. Mol. Cancer Ther. 10:1185–1193, 2011.

    Google Scholar 

  18. Bertozzi, S., A. P. Londero, C. Cedolini, A. Uzzau, L. Seriau, S. Bernardi, S. Bacchetti, E. M. Pasqual, and A. Risaliti. Prevalence, risk factors, and prognosis of peritoneal metastasis from breast cancer. Springerplus 4:1–8, 2015.

    Google Scholar 

  19. Bierie, B., and H. L. Moses. Tumour microenvironment—TGFΒ: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6:506–520, 2006.

    Google Scholar 

  20. Bochet, L., A. Meulle, S. Imbert, B. Salles, P. Valet, and C. Muller. Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem. Biophys. Res. Commun. 411:102–106, 2011.

    Google Scholar 

  21. Borten, M. A., S. S. Bajikar, N. Sasaki, H. Clevers, and K. A. Janes. Automated brightfield morphometry of 3D organoid populations by OrganoSeg. Sci. Rep. 8:1–10, 2018.

    Google Scholar 

  22. Bourhis, J., W. J. Sozzi, P. G. Jorge, O. Gaide, C. Bailat, F. Duclos, D. Patin, M. Ozsahin, F. Bochud, J. F. Germond, R. Moeckli, and M. C. Vozenin. Treatment of a first patient with FLASH-radiotherapy. Radiother. Oncol. 139:18–22, 2019.

    Google Scholar 

  23. Boutin, M. E., T. C. Voss, S. A. Titus, K. Cruz-Gutierrez, S. Michael, and M. Ferrer. A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models. Sci. Rep. 8:1–14, 2018.

    Google Scholar 

  24. Brown, J. M., and J. C. Probert. Long-term recovery of connective tissue after irradiation. Radiology 108:205–207, 1973.

    Google Scholar 

  25. Brown, P. D., S. Pugh, N. N. Laack, J. S. Wefel, D. Khuntia, C. Meyers, A. Choucair, S. Fox, J. H. Suh, D. Roberge, V. Kavadi, S. M. Bentzen, M. P. Mehta, and D. Watkins-bruner. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro. Oncol. 15:1429–1437, 2013.

    Google Scholar 

  26. Camphausen, K., M. A. Moses, C. Ménard, M. Sproull, W. D. Beecken, J. Folkman, and M. S. O’Reilly. Radiation abscopal antitumor effect is mediated through p53. Cancer Res. 63:1990–1993, 2003.

    Google Scholar 

  27. Casey, J., X. Yue, T. D. Nguyen, A. Acun, V. R. Zellmer, S. Zhang, and P. Zorlutuna. 3D hydrogel-based microwell arrays as a tumor microenvironment model to study breast cancer growth. Biomed. Mater. 12:1–12, 2017.

    Google Scholar 

  28. Centenera, M. M., T. E. Hickey, S. Jindal, N. K. Ryan, P. Ravindranathan, H. Mohammed, J. L. Robinson, M. J. Schiewer, S. Ma, P. Kapur, P. D. Sutherland, C. E. Hoffman, C. G. Roehrborn, L. G. Gomella, J. S. Carroll, S. N. Birrell, K. E. Knudsen, R. V. Ganesh, L. M. Butler, and W. D. Tilley. A patient-derived explant (PDE) model of hormone-dependent cancer. Mol. Oncol. 12:1608–1622, 2018.

    Google Scholar 

  29. Chatterjee, S., P. Basak, E. Buchel, L. C. Murphy, and A. Raouf. A robust cell culture system for large scale feeder cell-free expansion of human breast epithelial progenitors. Stem Cell Res. Ther. 9:1–10, 2018.

    Google Scholar 

  30. Chen, C. S., M. Mrksich, S. Huang, G. M. Whitesides, and D. E. Ingber. Geometric control of cell life and death. Science 276:1425–1428, 1997.

    Google Scholar 

  31. Chida, S., K. Okada, N. Suzuki, C. Komori, and Y. Shimada. Infiltration by macrophages and lymphocytes in transplantable mouse sarcoma after irradiation with high-intensity focused ultrasound. Anticancer Res. 29:3877–3882, 2009.

    Google Scholar 

  32. Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154:274–284, 2013.

    Google Scholar 

  33. Cline, J., G. Dugan, J. Bourland, D. Perry, J. Stitzel, A. Weaver, C. Jiang, A. Tovmasyan, K. Owzar, I. Spasojevic, I. Batinic-Haberle, and Z. Vujaskovic. Post-irradiation treatment with a superoxide dismutase mimic, MnTnHex-2-PyP5+, mitigates radiation injury in the lungs of non-human primates after whole-thorax exposure to ionizing radiation. Antioxidants 7:1–17, 2018.

    Google Scholar 

  34. De Ruysscher, D., G. Niedermann, N. G. Burnet, S. Siva, A. W. M. Lee, and F. Hegi-Johnson. Radiotherapy toxicity. Nat. Rev. Dis. Prim. 13:1–20, 2019.

    Google Scholar 

  35. Dekkers, J. F., M. Alieva, L. M. Wellens, H. C. R. Ariese, P. R. Jamieson, A. M. Vonk, G. D. Amatngalim, H. Hu, K. C. Oost, H. J. G. Snippert, J. M. Beekman, E. J. Wehrens, J. E. Visvader, H. Clevers, and A. C. Rios. High-resolution 3D imaging of fixed and cleared organoids. Nat. Protoc. 14:1756–1771, 2019.

    Google Scholar 

  36. Demaria, S., B. Ng, M. L. Devitt, J. S. Babb, N. Kawashima, L. Liebes, and S. C. Formenti. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58:862–870, 2004.

    Google Scholar 

  37. Dijkstra, K. K., C. M. Cattaneo, F. Weeber, M. Chalabi, J. van de Haar, L. F. Fanchi, M. Slagter, D. L. van der Velden, S. Kaing, S. Kelderman, N. van Rooij, M. E. van Leerdam, A. Depla, E. F. Smit, K. J. Hartemink, R. de Groot, M. C. Wolkers, N. Sachs, P. Snaebjornsson, K. Monkhorst, J. Haanen, H. Clevers, T. N. Schumacher, and E. E. Voest. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174:1586–1598, 2018.

    Google Scholar 

  38. Dragun, A. E., J. Pan, S. N. Rai, B. Kruse, and D. Jain. Locoregional recurrence in patients with triple-negative breast cancer: preliminary results of a single institution study. Am. J. Clin. Oncol. Cancer Clin. Trials 34:231–237, 2011.

    Google Scholar 

  39. Durante, M., and S. C. Formenti. Radiation-induced chromosomal aberrations and immunotherapy: micronuclei, cytosolic DNA, and interferon-production pathway. Front. Oncol. 8:1–9, 2018.

    Google Scholar 

  40. Ewald, A. J., A. Brenot, M. Duong, B. S. Chan, and Z. Werb. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell 14:570–581, 2008.

    Google Scholar 

  41. Fajardo, L. F. The pathology of ionizing radiation as defined by morphologic patterns. Acta Oncol. 44:13–22, 2005.

    Google Scholar 

  42. Fessenden, T. B., Y. Beckham, M. Perez-Neut, A. H. Chourasia, K. F. Macleod, P. W. Oakes, and M. L. Gardel. Dia1-dependent adhesions are required for invasion by epithelial tissues. J. Cell Biol. 217:1485–1502, 2018.

    Google Scholar 

  43. Feys, L., B. Descamps, C. Vanhove, A. Vral, L. Veldeman, S. Vermeulen, C. De Wagter, M. Bracke, and O. De Wever. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling. Oncotarget 6:26615–26632, 2015.

    Google Scholar 

  44. Folkman, J., and K. Camphausen. What does radiotherapy do to endothelial cells? Science 293:227–228, 2001.

    Google Scholar 

  45. Furuta, S., G. Ren, J. H. Mao, and M. J. Bissell. Laminin signals initiate the reciprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs. Elife 7:1–40, 2018.

    Google Scholar 

  46. Garcia-Barros, M., F. Paris, C. Cordon-Cardo, D. Lyden, S. Rafii, A. Haimovitz-Friedman, Z. Fuks, and R. Kolesnick. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159, 2003.

    Google Scholar 

  47. Grither, W. R., and G. D. Longmore. Inhibition of tumor–microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain. Proc. Natl. Acad. Sci. 115:E7786–E7794, 2018.

    Google Scholar 

  48. Groselj, B., J.-L. Ruan, H. Scott, J. Gorrill, J. Nicholson, J. Kelly, S. Anbalagan, J. Thompson, M. R. L. Stratford, S. J. Jevons, E. M. Hammond, C. L. Scudamore, M. Kerr, and A. E. Kiltie. Radiosensitization In vivo by histone deacetylase inhibition with no increase in early normal tissue radiation toxicity. Mol. Cancer Ther. 17:381–392, 2017.

    Google Scholar 

  49. Grudzenski, S., A. Raths, S. Conrad, C. E. Rübe, and M. Löbrich. Inducible response required for repair of low-dose radiation damage in human fibroblasts. Proc. Natl. Acad. Sci. 107:14205–14210, 2010.

    Google Scholar 

  50. Guiet, R., E. Van Goethem, C. Cougoule, S. Balor, A. Valette, T. Al Saati, C. A. Lowell, V. Le Cabec, and I. Maridonneau-Parini. The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J. Immunol. 187:3806–3814, 2011.

    Google Scholar 

  51. Hacker, B. C., J. D. Gomez, C. A. SilveraBatista, and M. Rafat. Growth and characterization of irradiated organoids from mammary glands. J. Vis. Exp. 147:e59293, 2019.

    Google Scholar 

  52. Hama, H., H. Hioki, K. Namiki, T. Hoshida, H. Kurokawa, F. Ishidate, T. Kaneko, T. Akagi, T. Saito, T. Saido, and A. Miyawaki. ScaleS: an optical clearing palette for biological imaging. Nat. Neurosci. 18:1518–1529, 2015.

    Google Scholar 

  53. Han, Y. L., P. Ronceray, G. Xu, A. Malandrino, R. D. Kamm, M. Lenz, C. P. Broedersz, and M. Guo. Cell contraction induces long-ranged stress stiffening in the extracellular matrix. Proc. Natl. Acad. Sci. 115:4075–4080, 2018.

    Google Scholar 

  54. Hanahan, D., and R. A. Weinberg. Hallmarks of cancer: the next generation. Cell 144:646–674, 2011.

    Google Scholar 

  55. Huang, Q., F. Li, X. Liu, W. Li, W. Shi, F. F. Liu, B. O’Sullivan, Z. He, Y. Peng, A. C. Tan, L. Zhou, J. Shen, G. Han, X. J. Wang, J. Thorburn, A. Thorburn, A. Jimeno, D. Raben, J. S. Bedford, and C. Y. Li. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17:860–866, 2011.

    Google Scholar 

  56. Huang, X., F. Yuan, M. Liang, H. W. Lo, M. L. Shinohara, C. Robertson, and P. Zhong. M-HIFU inhibits tumor growth, suppresses STAT3 activity and enhances tumor specific immunity in a transplant tumor model of prostate cancer. PLoS ONE 7:1–11, 2012.

    Google Scholar 

  57. Huebner, R. J., N. M. Neumann, and A. J. Ewald. Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration. Development 143:983–995, 2016.

    Google Scholar 

  58. Hwang, P. Y., A. Brenot, A. C. King, G. D. Longmore, and S. C. George. Randomly distributed K14+ breast tumor cells polarize to the leading edge and guide collective migration in response to chemical and mechanical environmental cues. Cancer Res. 79:1899–1912, 2019.

    Google Scholar 

  59. Jadaliha, M., O. Gholamalamdari, W. Tang, Y. Zhang, A. Petracovici, Q. Hao, A. Tariq, T. G. Kim, S. E. Holton, D. K. Singh, X. L. Li, S. M. Freier, S. Ambs, R. Bhargava, A. Lal, S. G. Prasanth, J. Ma, and K. V. Prasanth. A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. PLoS Genet. 14:e1007802, 2018.

    Google Scholar 

  60. Jalili-Firoozinezhad, S., R. Prantil-Baun, A. Jiang, R. Potla, T. Mammoto, J. C. Weaver, T. C. Ferrante, H. J. Kim, J. M. S. Cabral, O. Levy, and D. E. Ingber. Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. Cell Death Dis. 9:1–14, 2018.

    Google Scholar 

  61. Jamieson, P. R., J. F. Dekkers, A. C. Rios, N. Y. Fu, G. J. Lindeman, and J. E. Visvader. Derivation of a robust mouse mammary organoid system for studying tissue dynamics. Development 144:1065–1071, 2016.

    Google Scholar 

  62. Jardé, T., B. Lloyd-Lewis, M. Thomas, H. Kendrick, L. Melchor, L. Bougaret, P. D. Watson, K. Ewan, M. J. Smalley, and T. C. Dale. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nat. Commun. 7:1–14, 2016.

    Google Scholar 

  63. Jiang, Y., T. Verbiest, A. M. Devery, S. M. Bokobza, A. M. Weber, K. B. Leszczynska, E. M. Hammond, and A. J. Ryan. Hypoxia potentiates the radiation-sensitizing effect of olaparib in human non-small cell lung cancer xenografts by contextual synthetic lethality. Int. J. Radiat. Oncol. Biol. Phys. 95:772–781, 2016.

    Google Scholar 

  64. Ke, M. T., S. Fujimoto, and T. Imai. SeeDB: A simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction. Nat. Neurosci. 16:1154–1161, 2013.

    Google Scholar 

  65. Kim, M. Y., T. Oskarsson, S. Acharyya, D. X. Nguyen, X. H. F. Zhang, L. Norton, and J. Massagué. Tumor self-seeding by circulating cancer cells. Cell 139:1315–1326, 2009.

    Google Scholar 

  66. Kioi, M., J. M. Brown, H. Vogel, G. Schultz, R. M. Hoffman, and G. R. Harsh. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120:694–705, 2010.

    Google Scholar 

  67. Klingelhutz, A. J., F. A. Gourronc, A. Chaly, D. A. Wadkins, A. J. Burand, K. R. Markan, S. O. Idiga, M. Wu, M. J. Potthoff, and J. A. Ankrum. Scaffold-free generation of uniform adipose spheroids for metabolism research and drug discovery. Sci. Rep. 8:1–12, 2018.

    Google Scholar 

  68. Koledova, Z. 3D coculture of mammary organoids with fibrospheres: a model for studying epithelial–stromal interactions during mammary branching morphogenesis. In: Methods in Molecular Biology, edited by Z. Koledova. New York, NY: Humana Press, 2017.

    Google Scholar 

  69. Kopanska, K. S., Y. Alcheikh, R. Staneva, D. Vignjevic, and T. Betz. Tensile forces originating from cancer spheroids facilitate tumor invasion. PLoS ONE 11:1–23, 2016.

    Google Scholar 

  70. Kuen, J., D. Darowski, T. Kluge, and M. Majety. Pancreatic cancer cell/fibroblast co-culture induces M2 like macrophages that influence therapeutic response in a 3D model. PLoS One 12:1–19, 2017.

    Google Scholar 

  71. LaBarge, M. A., J. C. Garbe, and M. R. Stampfer. Processing of human reduction mammoplasty and mastectomy tissues for cell culture. J. Vis. Exp. 71:e50011, 2013.

    Google Scholar 

  72. Laperrousaz, B., S. Porte, S. Gerbaud, V. Härmä, F. Kermarrec, V. Hourtane, F. Bottausci, X. Gidrol, and N. Picollet-D’Hahan. Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens. Nucleic Acids Res. 46:1–13, 2018.

    Google Scholar 

  73. Lasfargues, E. Cultivation and behavior in vitro of the normal mammary epithelium of the adult mouse. Anat. Rec. 127:117–129, 1957.

    Google Scholar 

  74. Linde, N., M. Casanova-Acebes, M. S. Sosa, A. Mortha, A. Rahman, E. Farias, K. Harper, E. Tardio, I. ReyesTorres, J. Jones, J. Condeelis, M. Merad, and J. A. Aguirre-Ghiso. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat. Commun. 9:1–14, 2018.

    Google Scholar 

  75. Linnemann, J. R., H. Miura, L. K. Meixner, M. Irmler, U. J. Kloos, B. Hirschi, H. S. Bartsch, S. Sass, J. Beckers, F. J. Theis, C. Gabka, K. Sotlar, and C. H. Scheel. Quantification of regenerative potential in primary human mammary epithelial cells. Development 142:3239–3251, 2015.

    Google Scholar 

  76. Liu, H. L., H. Y. Hsieh, L. A. Lu, C. W. Kang, M. F. Wu, and C. Y. Lin. Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response. J. Transl. Med. 10:1–14, 2012.

    Google Scholar 

  77. Loi, S., S. Michiels, R. Salgado, N. Sirtaine, V. Jose, D. Fumagalli, P. L. Kellokumpu-Lehtinen, P. Bono, V. Kataja, C. Desmedt, M. J. Piccart, S. Loibl, C. Denkert, M. J. Smyth, H. Joensuu, and C. Sotiriou. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25:1544–1550, 2014.

    Google Scholar 

  78. López Alfonso, J. C., S. Parsai, N. Joshi, A. Godley, C. Shah, S. A. Koyfman, J. J. Caudell, C. D. Fuller, H. Enderling, and J. G. Scott. Temporally feathered intensity-modulated radiation therapy: a planning technique to reduce normal tissue toxicity. Med. Phys. 45:3466–3474, 2018.

    Google Scholar 

  79. Lowery, A., M. Kell, R. Glynn, M. Kerin, and K. Sweeney. Locoregional recurrence after breast cancer surgery : a systematic review by receptor phenotype. Breast Cancer Res. Treat. 133:831–841, 2012.

    Google Scholar 

  80. Lu, L., M. Jiang, C. Zhu, J. He, and S. Fan. Amelioration of whole abdominal irradiation-induced intestinal injury in mice with 3,3′-Diindolylmethane (DIM). Free Radic. Biol. Med. 130:244–255, 2019.

    Google Scholar 

  81. Malandrino, A., M. Mak, R. D. Kamm, and E. Moeendarbary. Complex mechanics of the heterogeneous extracellular matrix in cancer. Extrem. Mech. Lett. 21:25–34, 2018.

    Google Scholar 

  82. Malandrino, A., X. Trepat, R. D. Kamm, and M. Mak. Dynamic filopodial forces induce accumulation, damage, and plastic remodeling of 3D extracellular matrices. PLoS Comput. Biol. 15:1–26, 2019.

    Google Scholar 

  83. Martin, I., D. Wendt, and M. Heberer. The role of bioreactors in tissue engineering. Trends Biotechnol. 22:80–86, 2004.

    Google Scholar 

  84. Meng, L., Y. Cheng, X. Tong, S. Gan, Y. Ding, Y. Zhang, C. Wang, L. Xu, Y. Zhu, J. Wu, Y. Hu, and A. Yuan. Tumor oxygenation and hypoxia inducible factor-1 functional inhibition via a reactive oxygen species responsive nanoplatform for enhancing radiation therapy and abscopal effects. ACS Nano 12:8308–8322, 2018.

    Google Scholar 

  85. Metcalfe, C., N. M. Kljavin, R. Ybarra, and F. J. De Sauvage. Lgr5+stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14:149–159, 2014.

    Google Scholar 

  86. Miller, D. H., D. X. Jin, E. S. Sokol, J. R. Cabrera, D. A. Superville, R. A. Gorelov, C. Kuperwasser, and P. B. Gupta. BCL11B drives human mammary stem cell self-renewal in vitro by inhibiting basal differentiation. Stem Cell Rep. 10:1131–1145, 2018.

    Google Scholar 

  87. Miller, J. S., K. R. Stevens, M. T. Yang, B. M. Baker, D. H. T. Nguyen, D. M. Cohen, E. Toro, A. A. Chen, P. A. Galie, X. Yu, R. Chaturvedi, S. N. Bhatia, and C. S. Chen. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11:768–774, 2012.

    Google Scholar 

  88. Montay-Gruel, P., A. Bouchet, M. Jaccard, D. Patin, R. Serduc, W. Aim, K. Petersson, B. Petit, C. Bailat, J. Bourhis, E. Bräuer-Krisch, and M. C. Vozenin. X-rays can trigger the FLASH effect: ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice. Radiother. Oncol. 129:582–588, 2018.

    Google Scholar 

  89. Montay-Gruel, P., K. Petersson, M. Jaccard, G. Boivin, J. F. Germond, B. Petit, R. Doenlen, V. Favaudon, F. Bochud, C. Bailat, J. Bourhis, and M. C. Vozenin. Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy/s. Radiother. Oncol. 124:365–369, 2017.

    Google Scholar 

  90. Morgan, M. M., M. K. Livingston, J. W. Warrick, E. M. Stanek, E. T. Alarid, D. J. Beebe, and B. P. Johnson. Mammary fibroblasts reduce apoptosis and speed estrogen-induced hyperplasia in an organotypic MCF7-derived duct model. Sci. Rep. 8:1–13, 2018.

    Google Scholar 

  91. Morini, J., G. Babini, S. Barbieri, G. Baiocco, and A. Ottolenghi. The interplay between radioresistant Caco-2 cells and the immune system increases epithelial layer permeability and alters signaling protein spectrum. Front. Immunol. 8:1–12, 2017.

    Google Scholar 

  92. Nagle, P. W., N. A. Hosper, L. Barazzuol, A. L. Jellema, M. Baanstra, M. J. Van Goethem, S. Brandenburg, U. Giesen, J. A. Langendijk, P. Van Luijk, and R. P. Coppes. Lack of DNA damage response at low radiation doses in adult stem cells contributes to organ dysfunction. Clin. Cancer Res. 24:6583–6593, 2018.

    Google Scholar 

  93. Nguyen, D. H., H. A. Oketch-Rabah, I. Illa-Bochaca, F. C. Geyer, J. S. Reis-Filho, J. H. Mao, S. A. Ravani, J. Zavadil, A. D. Borowsky, D. J. Jerry, K. A. Dunphy, J. H. Seo, S. Haslam, D. Medina, and M. H. Barcellos-Hoff. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19:640–651, 2011.

    Google Scholar 

  94. Nguyen-Ngoc, K.-V., K. J. Cheung, A. Brenot, E. R. Shamir, R. S. Gray, W. C. Hines, P. Yaswen, Z. Werb, and A. J. Ewald. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. Proc. Natl. Acad. Sci. 89:E2595–E2604, 2012.

    Google Scholar 

  95. Nguyen-Ngoc, K.-V., E. R. Shamir, R. J. Huebner, J. N. Beck, K. J. Cheung, and A. J. Ewald. 3D culture assays of murine mammary branching morphogenesis and epithelial invasion. In: Tissue Morphogenesis: Methods and Protocols, edited by C. M. Nelson. New York: Springer, 2015, pp. 135–162.

    Google Scholar 

  96. Noël, G., C. Godon, M. Fernet, N. Giocanti, F. Mégnin-Chanet, and V. Favaudon. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol. Cancer Ther. 5:564–574, 2006.

    Google Scholar 

  97. Nozaki, K., W. Mochizuki, Y. Matsumoto, T. Matsumoto, M. Fukuda, T. Mizutani, M. Watanabe, and T. Nakamura. Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes. J. Gastroenterol. 51:206–213, 2016.

    Google Scholar 

  98. Ohuchida, K., K. Mizumoto, M. Murakami, L. W. Qian, N. Sato, E. Nagai, K. Matsumoto, T. Nakamura, and M. Tanaka. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64:3215–3222, 2004.

    Google Scholar 

  99. Panciera, T., L. Azzolin, A. Fujimura, D. Di Biagio, C. Frasson, S. Bresolin, S. Soligo, G. Basso, S. Bicciato, A. Rosato, M. Cordenonsi, and S. Piccolo. Induction of expandable tissue-specific stem/progenitor cells through transient expression of YAP/TAZ. Cell Stem Cell 19:725–737, 2016.

    Google Scholar 

  100. Paris, F., Z. Fuks, A. Kang, P. Capodieci, G. Juan, D. Ehlelter, A. Halmovitz-Friedman, C. Cordon-Cardo, and R. Kolesnick. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293:293–297, 2001.

    Google Scholar 

  101. Poglio, S., S. Galvani, S. Bour, M. André, B. Prunet-Marcassus, L. Pénicaud, L. Casteilla, and B. Cousin. Adipose tissue sensitivity to radiation exposure. Am. J. Pathol. 174:44–53, 2009.

    Google Scholar 

  102. Powell, D. R., and A. Huttenlocher. Neutrophils in the tumor microenvironment. Trends Immunol. 37:41–52, 2016.

    Google Scholar 

  103. Rafat, M., T. A. Aguilera, M. Vilalta, L. L. Bronsart, L. A. Soto, R. von Eyben, M. A. Golla, Y. Ahrari, S. Melemenidis, A. Afghahi, M. J. Jenkins, A. W. Kurian, K. C. Horst, A. J. Giaccia, and E. E. Graves. Macrophages promote circulating tumor cell–mediated local recurrence following radiotherapy in immunosuppressed patients. Cancer Res. 78:4241–4252, 2018.

    Google Scholar 

  104. Ray, G., S. Batra, N. K. Shukla, S. Deo, V. Raina, S. Ashok, and S. A. Husain. Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res. Treat. 59:163–170, 2000.

    Google Scholar 

  105. Rodemann, H. P., and M. A. Blaese. Responses of normal cells to ionizing radiation. Semin. Radiat. Oncol. 17:81–88, 2007.

    Google Scholar 

  106. Rodney Withers, H. Biological basis of radiation therapy for cancer. Lancet 339:156–159, 1992.

    Google Scholar 

  107. Rossi, G., A. Manfrin, and M. P. Lutolf. Progress and potential in organoid research. Nat. Rev. Genet. 19:671–687, 2018.

    Google Scholar 

  108. Sachs, N., J. de Ligt, O. Kopper, E. Gogola, G. Bounova, F. Weeber, A. V. Balgobind, K. Wind, A. Gracanin, H. Begthel, J. Korving, R. van Boxtel, A. A. Duarte, D. Lelieveld, A. van Hoeck, R. F. Ernst, F. Blokzijl, I. J. Nijman, M. Hoogstraat, M. van de Ven, D. A. Egan, V. Zinzalla, J. Moll, S. F. Boj, E. E. Voest, L. Wessels, P. J. van Diest, S. Rottenberg, R. G. J. Vries, E. Cuppen, and H. Clevers. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172:373–386, 2018.

    Google Scholar 

  109. Sato, T., and H. Clevers. SnapShot: Growing organoids from stem cells. Cell 161:1700–1700.e1, 2015.

    Google Scholar 

  110. Sato, T., D. E. Stange, M. Ferrante, R. G. J. Vries, J. H. Van Es, S. Van Den Brink, W. J. Van Houdt, A. Pronk, J. Van Gorp, P. D. Siersema, and H. Clevers. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141:1762–1772, 2011.

    Google Scholar 

  111. Sayarath, M., M.-C. Vozenin, L. Caplier, J. Bourhis, C. Fouillade, P. Hupe, J. Hall, V. Favaudon, M.-F. Poupon, V. Monceau, J.-J. Fontaine, F. Pouzoulet, and I. Brito. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6:1–9, 2014.

    Google Scholar 

  112. Schaue, D., E. L. Kachikwu, and W. H. McBride. Cytokines in radiobiological responses: a review. Radiat. Res. 178:505–523, 2012.

    Google Scholar 

  113. Senra, J. M., B. A. Telfer, K. E. Cherry, C. M. McCrudden, D. G. Hirst, M. J. O’Connor, S. R. Wedge, and I. J. Stratford. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol. Cancer Ther. 10:1949–1958, 2011.

    Google Scholar 

  114. Shamir, E. R., E. Pappalardo, D. M. Jorgens, K. Coutinho, W. T. Tsai, K. Aziz, M. Auer, P. T. Tran, J. S. Bader, and A. J. Ewald. Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J. Cell Biol. 204:839–856, 2014.

    Google Scholar 

  115. Sherry, A. D., R. von Eyben, N. B. Newman, P. Gutkin, I. Mayer, K. Horst, A. B. Chakravarthy, and M. Rafat. Systemic inflammation after radiation predicts locoregional recurrence, progression, and mortality in stage II-III triple-negative breast cancer. Int. J. Radiat. Oncol. 2019. https://doi.org/10.1016/j/ijrobp.2019.11.398.

    Article  Google Scholar 

  116. Siegel, R. L., K. D. Miller, and A. Jemal. Cancer statistics, 2018. Cancer J. Clin. 69:7–34, 2019.

    Google Scholar 

  117. Simmons, D. A., F. M. Lartey, E. Schüler, M. Rafat, G. King, A. Kim, R. Ko, S. Semaan, S. Gonzalez, M. Jenkins, P. Pradhan, Z. Shih, J. Wang, R. von Eyben, E. E. Graves, P. G. Maxim, F. M. Longo, and B. W. Loo. Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation. Radiother. Oncol. 139:4–10, 2019.

    Google Scholar 

  118. Sirka, O. K., E. R. Shamir, and A. J. Ewald. Myoepithelial cells are a dynamic barrier to epithelial dissemination. J. Cell Biol. 217:3368–3381, 2018.

    Google Scholar 

  119. Skrzydlewska, E., S. Sulkowksi, M. Koda, B. Zalewski, L. Kanczuga-Koda, and M. Sulkowska. Lipid peroxidation and antioxidant status in colorecal cancer. World J Gastroenterol. 11:403–406, 2005.

    Google Scholar 

  120. Slonina, D., B. Biesaga, K. Urbanski, and Z. Kojs. Low-dose radiation response of primary keratinocytes and fibroblasts from patients with cervix cancer. Radiat. Res. 167:251–259, 2007.

    Google Scholar 

  121. Sofia Vala, I., L. R. Martins, N. Imaizumi, R. J. Nunes, J. Rino, F. Kuonen, L. M. Carvalho, C. Rüegg, I. M. Grillo, J. T. Barata, M. Mareel, and S. C. R. Santos. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLoS ONE 5:1–13, 2010.

    Google Scholar 

  122. Spill, F., C. Bakal, and M. Mak. Mechanical and systems biology of cancer. Comput. Struct. Biotechnol. J. 16:237–245, 2018.

    Google Scholar 

  123. Stephens, T. C., G. A. Currie, and J. H. Peacock. Repopulation of gamma-irradiated lewis lung carcinoma by malignant cells and host macrophage progenitors. Br. J. Cancer 38:573–582, 1978.

    Google Scholar 

  124. Szumiel, I. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int. J. Radiat. Biol. 91:1–12, 2015.

    Google Scholar 

  125. Taniguchi, C. M., Y. R. Miao, A. N. Diep, C. Wu, E. B. Rankin, T. F. Atwood, L. Xing, and A. J. Giaccia. PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci. Transl. Med. 6:1–9, 2014.

    Google Scholar 

  126. Tevis, K. M., R. J. Cecchi, Y. L. Colson, and M. W. Grinstaff. Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models. Acta Biomater. 50:271–279, 2017.

    Google Scholar 

  127. Tsai, K. K. C., E. Y. Y. Chuang, J. B. Little, and Z. M. Yuan. Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res. 65:6734–6744, 2005.

    Google Scholar 

  128. Tsikas, D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal. Biochem. 524:13–30, 2017.

    Google Scholar 

  129. Unver, N., and F. Mcallister. IL-6 family cytokines: key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev. 41:10–17, 2018.

    Google Scholar 

  130. van Luijk, P., S. Pringle, S. Brandenburg, V. V. Moiseenko, H. P. van der Laan, R. P. Coppes, J. Wu, J. A. Langendijk, M. J. Witjes, J. M. Schippers, J. O. Deasy, A. Hovan, A. van der Schaaf, M. Baanstra, H. Faber, and R. G. J. Kierkels. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci. Transl. Med. 7:1–8, 2015.

    Google Scholar 

  131. Vanpouille-Box, C., A. Alard, M. J. Aryankalayil, Y. Sarfraz, J. M. Diamond, R. J. Schneider, G. Inghirami, C. N. Coleman, S. C. Formenti, and S. Demaria. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8:1–15, 2017.

    Google Scholar 

  132. Venkatesulu, B. P., L. S. Mahadevan, M. L. Aliru, X. Yang, M. H. Bodd, P. K. Singh, S. W. Yusuf, J. Abe, and S. Krishnan. Radiation-induced endothelial vascular injury. JACC Basic Transl. Sci. 3:563–572, 2018.

    Google Scholar 

  133. Vilalta, M., M. Rafat, and E. E. Graves. Effects of radiation on metastasis and tumor cell migration. Cell. Mol. Life Sci. 73:2999–3007, 2016.

    Google Scholar 

  134. von Essen, C. F. Radiation enhancement of metastasis: a review. Clin. Exp. Metastasis 9:77–104, 1991.

    Google Scholar 

  135. Wang, X. Y., Z. H. Jin, B. W. Gan, S. W. Lv, M. Xie, and W. H. Huang. Engineering interconnected 3D vascular networks in hydrogels using molded sodium alginate lattice as the sacrificial template. Lab Chip 14:2709–2716, 2014.

    Google Scholar 

  136. Wang, X., Q. Sun, and J. Pei. Microfluidic-based 3D engineered microvascular networks and their applications in vascularized microtumor models. Micromachines 9:1–26, 2018.

    Google Scholar 

  137. Wang, F., V. M. Weaver, O. W. Petersen, C. A. Larabell, S. Dedhar, P. Briand, R. Lupu, and M. J. Bissell. Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc. Natl. Acad. Sci. 95:14821–14826, 1998.

    Google Scholar 

  138. Weigelt, B., J. L. Peterse, and L. J. Van’t Veer. Breast cancer metastasis: markers and models. Nat. Rev. Cancer 5:591–602, 2005.

    Google Scholar 

  139. Welsch, C. W. Review of the effects of dietary fat on experimental mammary gland tumorigenesis: role of lipid peroxidation. Free Radic. Biol. Med. 18:757–773, 1995.

    Google Scholar 

  140. Winslow, S., A. Scholz, P. Rappl, T. F. Brauß, C. Mertens, M. Jung, A. Weigert, B. Brüne, and T. Schmid. Macrophages attenuate the transcription of CYP1A1 in breast tumor cells and enhance their proliferation. PLoS ONE 14:1–12, 2019.

    Google Scholar 

  141. Wong, E., S. Chaudhry, and M. Rossi. Breast cancer. McMaster Pathophysiol. Rev., 2012.

  142. Wouters, B. G. Oncology scan-how radiation effects on cells in the stromal microenvironment influence tumor development, proliferation, and recovery. Int. J. Radiat. Oncol. Biol. Phys. 86:593–595, 2013.

    Google Scholar 

  143. Xu, K., and R. J. Buchsbaum. Isolation of mammary epithelial cells from three-dimensional mixed-cell spheroid co-culture. J. Vis. Exp. 62:e3760, 2012.

    Google Scholar 

  144. Zanoni, M., F. Piccinini, C. Arienti, A. Zamagni, S. Santi, R. Polico, A. Bevilacqua, and A. Tesei. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci. Rep. 6:1–11, 2016.

    Google Scholar 

  145. Zhang, Z., F. Jin, X. Lian, M. Li, G. Wang, B. Lan, H. He, G. D. Liu, Y. Wu, G. Sun, C. X. Xu, and Z. Z. Yang. Genistein promotes ionizing radiation-induced cell death by reducing cytoplasmic Bcl-xL levels in non-small cell lung cancer. Sci. Rep. 8:1–9, 2018.

    Google Scholar 

  146. Zhang, C., S. Wang, H. P. Israel, S. X. Yan, D. P. Horowitz, S. Crockford, D. Gidea-Addeo, K. S. Clifford Chao, K. Kalinsky, and E. P. Connolly. Higher locoregional recurrence rate for triple-negative breast cancer following neoadjuvant chemotherapy, surgery and radiotherapy. Springerplus 4:1–9, 2015.

    Google Scholar 

  147. Zhao, J., M. Griffin, J. Cai, S. Li, P. E. M. Bulter, and D. M. Kalaskar. Bioreactors for tissue engineering: an update. Biochem. Eng. J. 109:268–281, 2016.

    Google Scholar 

  148. Zhong, J., S. A. Krawczyk, R. Chaerkady, H. Huang, R. Goel, J. S. Bader, G. W. Wong, B. E. Corkey, and A. Pandey. Temporal profiling of the secretome during adipogenesis in humans. J. Proteome Res. 9:5228–5238, 2010.

    Google Scholar 

  149. Zubeldia-Plazaola, A., L. Recalde-Percaz, N. Moragas, M. Alcaraz, X. Chen, M. Mancino, P. Fernández-Nogueira, M. P. de Puig, F. Guzman, A. Noguera-Castells, A. López-Plana, E. Enreig, N. Carbó, V. Almendro, P. Gascón, P. Bragado, and G. Fuster. Glucocorticoids promote transition of ductal carcinoma in situ to invasive ductal carcinoma by inducing myoepithelial cell apoptosis. Breast Cancer Res. 20:1–16, 2018.

    Google Scholar 

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Acknowledgments

This work was financially supported by NIH Grant #R00CA201304.

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Benjamin C. Hacker and Marjan Rafat declare that they have no conflicts of interest.

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  1. Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA

    Benjamin C. Hacker & Marjan Rafat

  2. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA

    Marjan Rafat

  3. Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Marjan Rafat

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Hacker, B.C., Rafat, M. Organoids as Complex In Vitro Models for Studying Radiation-Induced Cell Recruitment. Cel. Mol. Bioeng. 13, 341–357 (2020). https://doi.org/10.1007/s12195-020-00625-0

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