An engineered tumor-on-a-chip device with breast cancer–immune cell interactions for assessing T-cell recruitment
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Abstract
Recruitment of immune cells to a tumor is determined by the complex interplay between cellular and noncellular components of the tumor microenvironment. Ex vivo platforms that enable identification of key components that promote immune cell recruitment to the tumor could advance the field significantly. Herein, we describe the development of a perfusable multicellular tumor-on-a-chip platform involving different cell populations. Cancer cells, monocytes, and endothelial cells were spatially confined within a gelatin hydrogel in a controlled manner by using 3D photopatterning. The migration of the encapsulated endothelial cells against a chemokine gradient created an endothelial layer around the constructs. Using this platform, we examined the effect of cancer cell–monocyte interaction on T-cell recruitment, where T cells were dispersed within the perfused media and allowed to infiltrate. The hypoxic environment in the spheroid cultures recruited more T cells compared with dispersed cancer cells. Moreover, the addition of monocytes to the cancer cells improved T-cell recruitment. The differences in T-cell recruitment were associated with differences in chemokine secretion including chemokines influencing the permeability of the endothelial barrier. This proof-of-concept study shows how integration of microfabrication, microfluidics, and 3D cell culture systems could be used for the development of tumor-on-a-chip platforms involving heterotypic cells and their application in studying recruitment of cells by the tumor-associated microenvironment. Significance: This study describes how tumor-on-chip platforms could be designed to create a heterogeneous mix of cells and noncellular components to study the effect of the tumor microenvironment on immune cell recruitment.
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In a perfusable microfluidic platform assessing breast cancer-immune cell interactions, T cell infiltration was greater when monocytes were present and when higher hypoxia was emulated using tumor spheroids instead of dispersed cancer cells.
“The results showed greater T cell in fi ltration when monocytes were present in the culture, and also when higher levels of hypoxia were emulated by using tumor spheroids instead of dispersed cancer cells [71].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [71]
T cell recruitment to tumor spheroids was increased in the presence of monocytes due to increased chemokine expression.
“T cell recruitment to tumor spheroids was shown to be increased in the presence of monocytes due to their increased chemokine expression [45].”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [45]
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Cites
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · see citing works
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413 · see citing works
Tumor-Associated Macrophages: From Mechanisms to Therapy
Noy, R., & Pollard, J. W. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.010 · Cited by 4,089 · see citing works
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · see citing works
The immune contexture in cancer prognosis and treatment
Fridman, W. H., Zitvogel, L., Sautès–Fridman, C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.101 · Cited by 2,263 · see citing works
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy
Nagarsheth, N., Wicha, M. S., & Zou, W. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.49 · Cited by 2,196 · see citing works
Gettinger, S. N., Horn, L., Gandhi, L., Spigel, D. R., Antonia, S. J., Rizvi, N. A., Powderly, J. D., Heist, R. S., Carvajal, R. D., Jackman, D. M., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.3708 · Cited by 1,180 · see citing works
Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment
Harlin, H., Meng, Y., Peterson, A. C., Zha, Y., Tretiakova, M., Slingluff, C., McKee, M., & Gajewski, T. F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2281 · Cited by 1,121 · see citing works
Genin, M., Clement, F., Fattaccioli, A., Raes, M., & Michiels, C. (2015) · BMC Cancer · doi:10.1186/s12885-015-1546-9 · Cited by 1,090 · see citing works
Hypoxia-Inducible Factors: Master Regulators of Cancer Progression
Schito, L., & Semenza, G. L. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.016 · Cited by 962 · see citing works
T-helper-1-cell cytokines drive cancer into senescence
Braumüller, H., Wieder, T., Brenner, E., Aßmann, S., Hahn, M., Alkhaled, M., Schilbach, K., Essmann, F., Kneilling, M., Griessinger, C., et al. (2013) · Nature · doi:10.1038/nature11824 · Cited by 720 · see citing works
Craddock, J. A., Lu, A., Bear, A. S., Pulè, M. A., Brenner, M. K., Rooney, C. M., & Foster, A. E. (2010) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181ee6675 · Cited by 514 · see citing works
Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity
DeNardo, D. G., Andreu, P., & Coussens, L. M. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9223-6 · Cited by 513 · see citing works
Targeting Macrophages in Cancer: From Bench to Bedside
Poh, A. R., & Ernst, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00049 · Cited by 497 · see citing works
Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors
Kochenderfer, J., & Rosenberg, S. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.46 · Cited by 467 · see citing works
Carlo, D. D., Aghdam, N., & Lee, L. P. (2006) · Analytical Chemistry · doi:10.1021/ac060541s · Cited by 458 · see citing works
Schlecker, E., Stojanovic, A., Eisen, C., Quack, C., Falk, C. S., Umansky, V., & Cerwenka, A. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201018 · Cited by 437 · see citing works
Noman, M. Z., Hasmim, M., Messai, Y., Terry, S., Kiéda, C., Janji, B., & Chouaı̈b, S. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00207.2015 · Cited by 405 · see citing works
Tumor-induced perturbations of cytokines and immune cell networks
Burkholder, B., Huang, R.-Y., Burgess, R., Luo, S., Jones, V. S., Zhang, W., Lv, Z., Gao, C., Wang, B.-L., Zhang, Y., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.01.004 · Cited by 354 · see citing works
Immune microenvironments in solid tumors: new targets for therapyPreprint
Shiao, S. L., Ganesan, A.-P., Rugo, H. S., & Coussens, L. M. (2011) · Genes & Development · doi:10.1101/gad.169029.111 · Cited by 320 · see citing works
Shirure, V. S., Bi, Y., Curtis, M. B., Lezia, A., Goedegebuure, M. M., Goedegebuure, S. P., Aft, R., Fields, R. C., & George, S. C. (2018) · Lab on a Chip · doi:10.1039/c8lc00596f · Cited by 316 · see citing works
Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs
Liou, G., Döppler, H. R., Necela, B. M., Krishna, M., Crawford, H. C., Raimondo, M., & Störz, P. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201301001 · Cited by 296 · see citing works
Raggi, F., Pelassa, S., Pierobon, D., Penco, F., Gattorno, M., Novelli, F., Eva, A., Varesio, L., Giovarelli, M., & Bosco, M. C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01097 · Cited by 282 · see citing works
IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways
Schraufstätter, I. U., Chung, J., & Burger, M. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.280.6.l1094 · Cited by 278 · see citing works
Ye, L., Chen, W., Bai, X., Xu, X., Zhang, Q., Xia, X., Sun, X., Li, G., Hu, Q., Fu, Q., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-0977 · Cited by 276 · see citing works
Defining the Role of Solid Stress and Matrix Stiffness in Cancer Cell Proliferation and Metastasis
Kalli, M., & Stylianopoulos, T. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00055 · Cited by 255 · see citing works
Chimeric antigen receptor T-cell therapy for solid tumors
Newick, K., Moon, E. K., & Albelda, S. Μ. (2016) · Molecular Therapy — Oncolytics · doi:10.1038/mto.2016.6 · Cited by 237 · see citing works
On the origin of myeloid-derived suppressor cells
Millrud, C. R., Bergenfelz, C., & Leandersson, K. (2016) · Oncotarget · doi:10.18632/oncotarget.12278 · Cited by 232 · see citing works
Gelatine Methacrylamide-Based Hydrogels: An Alternative Three-Dimensional Cancer Cell Culture System
Kaemmerer, E., Melchels, F. P. W., Holzapfel, B. M., Meckel, T., Hutmacher, D. W., & Loessner, D. (2014) · Acta Biomaterialia · doi:10.1016/j.actbio.2014.02.035 · Cited by 219 · see citing works
Cavo, M., Fato, M., Peñuela, L., Beltrame, F., Raiteri, R., & Scaglione, S. (2016) · Scientific Reports · doi:10.1038/srep35367 · Cited by 216 · see citing works
Methylphenidate Is Stereoselectively Hydrolyzed by Human Carboxylesterase CES1A1
Sun, Z., Murry, D. J., Sanghani, S. P., Davis, W. I., Kedishvili, N. Y., Zou, Q., Hurley, T. D., & BOSRON, W. F. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.067116 · Cited by 187 · see citing works
Chen, M. B., Hajal, C., Benjamin, D. C., Yu, C., Azizgolshani, H., Hynes, R. O., & Kamm, R. D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1715932115 · Cited by 183 · see citing works
Influence of Physical Properties of Biomaterials on Cellular Behavior
Lin, S., Sangaj, N. S., Razafiarison, T., Zhang, C., & Varghese, S. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0378-9 · Cited by 174 · see citing works
Self-citationEndothelial cells: From innocent bystanders to active participants in immune responses
Al-Soudi, A., Kaaij, M. H., & Tas, S. W. (2017) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.07.008 · Cited by 152 · see citing works
Yu, H., Huang, X., Ma, Y., Gao, M., Wang, O., Gao, T., Shen, Y., & Liu, X. (2013) · International Journal of Biological Sciences · doi:10.7150/ijbs.6996 · Cited by 150 · see citing works
Vascularized microfluidic organ-chips for drug screening, disease models and tissue engineering
Osaki, T., Sivathanu, V., & Kamm, R. D. (2018) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2018.03.011 · Cited by 141 · see citing works
The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer
Lee, D. W., Barrett, D. M., Mackall, C. L., Orentas, R. J., & Grupp, S. A. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1920 · Cited by 126 · see citing works
Aung, A., Gupta, G., Ghassemian, M., & Varghese, S. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30086 · Cited by 117 · see citing works
Self-citationBasal-like Breast Cancer Cells Induce Phenotypic and Genomic Changes in Macrophages
Stewart, D. A., Yang, Y., Makowski, L., & Troester, M. A. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0604 · Cited by 106 · see citing works
Kam, Y., Guess, C. M., Estrada, L., Weidow, B. L., & Quaranta, V. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-198 · Cited by 100 · see citing works
Lin, S., Wan, S., Sun, L., Hu, J., Fang, D., Zhao, R., Yuan, S., & Zhang, L. (2012) · Cancer Science · doi:10.1111/j.1349-7006.2012.02259.x · Cited by 92 · see citing works
Kumar, V., & Varghese, S. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201801198 · Cited by 68 · see citing works
Self-citation3D cardiac μtissues within a microfluidic device with real-time contractile stress readout
Aung, A., Bhullar, I. S., Theprungsirikul, J., Davey, S. K., Lim, H. L., Chiu, Y., Ma, X., Dewan, S., Lo, Y.-H., McCulloch, A. D., et al. (2015) · Lab on a Chip · doi:10.1039/c5lc00820d · Cited by 66 · see citing works
Self-citationCCL5 secreted by tumor associated macrophages may be a new target in treatment of gastric cancer
Ding, H., Zhao, L., Dai, S., Li, L., Wang, F., & Shan, B. (2015) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2015.12.004 · Cited by 64 · see citing works
Cesano, A., & Santoli, D. (1992) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/bf02631041 · Cited by 52 · see citing works
Chemotaxis-driven assembly of endothelial barrier in a tumor-on-a-chip platform
Aung, A., Theprungsirikul, J., Lim, H. L., & Varghese, S. (2016) · Lab on a Chip · doi:10.1039/c6lc00184j · Cited by 50 · see citing works
Self-citationMathematical Based Calculation of Drug Penetration Depth in Solid Tumors
Namazi, H., Kulish, V., Wong, A. S. H., & Nazeri, S. (2016) · BioMed Research International · doi:10.1155/2016/8437247 · Cited by 40 · see citing works
Davey, S. K., Aung, A., Agrawal, G., Lim, H. L., Kar, M., & Varghese, S. (2015) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2015.0179 · Cited by 30 · see citing works
Self-citationCytokine-induced killer cell trafficking to tumors: A chemokine-directed migration
Schmidt, T. L. (n.d.) · ProQuest Demo Repository · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 50 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research
Pinto, B., Henriques, A. C., Silva, P. M. A., & Bousbaa, H. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121186 · Cited by 440 · see citing works
3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions
Rodrigues, J., Heinrich, M. A., Teixeira, L. M., & Prakash, J. (2021) · Trends in Cancer · doi:10.1016/j.trecan.2020.10.009 · Cited by 405 · see citing works
“The results showed greater T cell infiltration when monocytes were present in the culture, and also when higher levels of hypoxia were emulated by using tumor spheroids instead of dispersed cancer cells [71].”
BackgroundMethodTumor microenvironment: barrier or opportunity towards effective cancer therapy
Tiwari, A., Trivedi, R., & Lin, S. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00866-3 · Cited by 391 · see citing works
Microfluidics for Drug Development: From Synthesis to Evaluation
Liu, Y., Sun, L., Zhang, H., Shang, L., & Zhao, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01289 · Cited by 209 · see citing works
Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy
Liu, Z., Zhou, Z., Dang, Q., Xu, H. M., Lv, J., Li, H., & Han, X. (2022) · Theranostics · doi:10.7150/thno.76854 · Cited by 198 · see citing works
3D Tumor Models and Their Use for the Testing of Immunotherapies
Boucherit, N., Gorvel, L., & Olive, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.603640 · Cited by 177 · see citing works
Emerging trends in organ-on-a-chip systems for drug screening
Wang, Y., Gao, Y., Pan, Y., Zhou, D., Liu, Y., Yin, Y. B., Yang, J., Wang, Y., & Song, Y. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.02.006 · Cited by 130 · see citing works
Advances in Organ-on-a-Chip Materials and Devices
Nahak, B. K., Mishra, A., Preetam, S., & Tiwari, A. (2022) · ACS Applied Bio Materials · doi:10.1021/acsabm.2c00041 · Cited by 124 · see citing works
Zhang, J., Tavakoli, H., Ma, L., Li, X., Han, L., & Li, X. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114365 · Cited by 110 · see citing works
Salemme, V., Centonze, G., Avalle, L., Natalini, D., Piccolantonio, A., Arina, P., Morellato, A., Ala, U., Taverna, D., Turco, E., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1170264 · Cited by 106 · see citing works
Microfluidic Organoids-on-a-Chip: Quantum Leap in Cancer Research
Düzağaç, F., Saorin, G., Memeo, L., Canzonieri, V., & Rizzolio, F. (2021) · Cancers · doi:10.3390/cancers13040737 · Cited by 94 · see citing works
Electrospun nanofibers in cancer research: from engineering of in vitro 3D cancer models to therapy
Cavo, M., Serio, F., Kale, N. R., D'Amone, E., Gigli, G., & del Mercato, L. L. (2020) · Biomaterials Science · doi:10.1039/d0bm00390e · Cited by 94 · see citing works
Engineering approaches for studying immune-tumor cell interactions and immunotherapy
Shelton, S. E., Nguyen, H. T., Barbie, D. A., & Kamm, R. D. (2021) · iScience · doi:10.1016/j.isci.2020.101985 · Cited by 93 · see citing works
3D cancer models: One step closer to in vitro human studies
Manduca, N., Maccafeo, E., Maria, R. D., Sistigu, A., & Musella, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1175503 · Cited by 95 · see citing works
Microfluidic high-throughput 3D cell culture
Ko, J., Park, D., Lee, J., Jung, S., Baek, K., Sung, K. E., Lee, J., & Jeon, N. L. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00163-8 · Cited by 88 · see citing works
Zhu, J., Ji, L., Chen, Y., Li, H., Huang, M., Dai, Z., Wang, J., Xiang, D., Fu, G., Lei, Z., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01354-9 · Cited by 87 · see citing works
Immunocompetent cancer-on-chip models to assess immuno-oncology therapy
Maulana, T. I., Kromidas, E., Wallstabe, L., Cipriano, M., Alb, M., Zaupa, C., Hudecek, M., Fogal, B., & Loskill, P. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.015 · Cited by 82 · see citing works
3D Culture Systems for Exploring Cancer Immunology
Fitzgerald, A. A., Li, E., & Weiner, L. M. (2020) · Cancers · doi:10.3390/cancers13010056 · Cited by 81 · see citing works
Proteinaceous Hydrogels for Bioengineering Advanced 3D Tumor Models
Blanco‐Fernandez, B., Gaspar, V. M., Engel, E., & Mano, J. F. (2021) · Advanced Science · doi:10.1002/advs.202003129 · Cited by 78 · see citing works
Zhou, Z., Pang, Y., Ji, J., He, J., Liu, T., Ouyang, L., Zhang, W., Zhang, X., Zhang, Z., Zhang, K., et al. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00896-4 · Cited by 73 · see citing works
Engineering microphysiological immune system responses on chips
Miller, C. P., Shin, W., Ahn, E. H., Kim, H. J., & Kim, D.-H. (2020) · Trends in biotechnology · doi:10.1016/j.tibtech.2020.01.003 · Cited by 74 · see citing works
Cell and tissue engineering in lymph nodes for cancer immunotherapy
Najibi, A. J., & Mooney, D. J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.023 · Cited by 73 · see citing works
Shah, S., & D’Souza, G. G. M. (2025) · Cells · doi:10.3390/cells14100732 · Cited by 66 · see citing works
“Beyond fibroblasts, similar strategies have been used in immune-tumor spheroids to investigate how macrophages or T cells migrate in response to tumor-derived chemokines, influencing immune suppression, matrix remodeling, or drug resistance [289].”
Cancer-on-chip models for metastasis: importance of the tumor microenvironment
Jouybar, M., de Winde, C. M., Wolf, K., Friedl, P., Mebius, R. E., & den Toonder, J. M. J. (2024) · Trends in Biotechnology · doi:10.1016/j.tibtech.2023.10.001 · Cited by 66 · see citing works
Jeong, S. Y., & Kang, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914609 · Cited by 70 · see citing works
Tumor-on-a-chip platforms to study cancer–immune system crosstalk in the era of immunotherapy
Parlato, S., Grisanti, G., Sinibaldi, G., Peruzzi, G., Casciola, C. M., & Gabriele, L. (2020) · Lab on a Chip · doi:10.1039/d0lc00799d · Cited by 67 · see citing works
Marzagalli, M., Pelizzoni, G., Fedi, A., Vitale, C., Fontana, F., Bruno, S., Poggi, A. D., Dondero, A., Aiello, M., Castriconi, R., et al. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.945149 · Cited by 63 · see citing works
3D Tumor Spheroid and Organoid to Model Tumor Microenvironment for Cancer Immunotherapy
Zhu, Y., Kang, E., Wilson, M., Basso, T., Chen, E., Yu, Y., & Li, Y.-R. (2022) · Organoids · doi:10.3390/organoids1020012 · Cited by 60 · see citing works
Song, J., Choi, H., Koh, S. K., Park, D., Yu, J., Kang, H., Kim, Y., Cho, D., & Jeon, N. L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.733317 · Cited by 59 · see citing works
3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment
Franchi-Mendes, T., Eduardo, R., Domenici, G., & Brito, C. (2021) · Cancers · doi:10.3390/cancers13184610 · Cited by 57 · see citing works
In vitro immunity: an overview of immunocompetent organ-on-chip models
Morrison, A. I., Sjoerds, M. J., Vonk, L. A., Gibbs, S., & Koning, J. J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1373186 · Cited by 56 · see citing works
The Variety of 3D Breast Cancer Models for the Study of Tumor Physiology and Drug Screening
Fröhlich, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087116 · Cited by 50 · see citing works
Micro-engineering and nano-engineering approaches to investigate tumour ecosystems
Kim, M., Panagiotakopoulou, M., Chen, C., Ruiz, S. B., Ganesh, K., Tammela, T., & Heller, D. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00593-3 · Cited by 49 · see citing works
Advances in the application of 3D tumor models in precision oncology and drug screening
Guan, X., & Huang, S. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.1021966 · Cited by 44 · see citing works
Engineering Breast Cancer On-chip—Moving Toward Subtype Specific Models
Moccia, C., & Haase, K. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.694218 · Cited by 34 · see citing works
Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)
Malik, M., Yang, Y., Fathi, P., Mahler, G. J., & Esch, M. B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.721338 · Cited by 43 · see citing works
Engineering in vitro immune-competent tissue models for testing and evaluation of therapeutics
Hammel, J. H., Zatorski, J. M., Cook, S. R., Pompano, R. R., & Munson, J. M. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114111 · Cited by 40 · see citing works
Microphysiological systems for solid tumor immunotherapy: opportunities and challenges
Abizanda-Campo, S., Virumbrales-Muñoz, M., Humayun, M., Mármol, I., Beebe, D. J., Ochoa, I., Oliván, S., & Ayuso, J. M. (2023) · Microsystems & Nanoengineering · doi:10.1038/s41378-023-00616-x · Cited by 41 · see citing works
Shen, P., Jia, Y., Zhou, W., Zheng, W., Wu, Y., Qu, S., Du, S., Wang, S., Shi, H., Sun, J., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.04.010 · Cited by 42 · see citing works
Ravi, K., Manoharan, T. J. M., Wang, K.-C., Pockaj, B. A., & Nikkhah, M. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122428 · Cited by 42 · see citing works
Ringquist, R., Ghoshal, D., Jain, R., & Roy, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114003 · Cited by 39 · see citing works
Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology
Xie, H., Appelt, J. W., & Jenkins, R. W. (2021) · Cancers · doi:10.3390/cancers13236052 · Cited by 39 · see citing works
Ortiz-Cárdenas, J. E., Zatorski, J. M., Arneja, A., Montalbine, A. N., Munson, J. M., Luckey, C. J., & Pompano, R. R. (2022) · Organs-on-a-Chip · doi:10.1016/j.ooc.2022.100018 · Cited by 37 · see citing works
An In Vitro Microfluidic Alveolus Model to Study Lung Biomechanics
Kumar, V., Perikamana, S. K. M., Tata, A., Hoque, J., Gilpin, A., Tata, P. R., & Varghese, S. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.848699 · Cited by 36 · see citing works
Self-citationSampaio, A. R., Maia, R., Ciardulli, M. C., Santos, H. A., & Sarmento, B. F. C. C. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.102053 · Cited by 35 · see citing works
Human immunocompetent choroid-on-chip: a novel tool for studying ocular effects of biological drugs
Cipriano, M., Schlünder, K., Probst, C., Linke, K., Weiß, M., Fischer, M. J., Mesch, L., Achberger, K., Liebau, S., Mesquida, M., et al. (2022) · Communications Biology · doi:10.1038/s42003-021-02977-3 · Cited by 35 · see citing works
A 3D pancreatic tumor model to study T cell infiltration
Mollica, H., Teo, Y. J., Tan, A. S. M., Tan, D. Z. M., Decuzzi, P., Pavesi, A., & Adriani, G. (2021) · Biomaterials Science · doi:10.1039/d1bm00210d · Cited by 32 · see citing works
On-chip modeling of tumor evolution: Advances, challenges and opportunities
Li, C., Holman, J. B., Shi, Z., Qiu, B., & Ding, W. (2023) · Materials Today Bio · doi:10.1016/j.mtbio.2023.100724 · Cited by 32 · see citing works
Wu, Y., Zhou, Y., Qin, X., & Liu, Y. (2021) · Biomicrofluidics · doi:10.1063/5.0062697 · Cited by 33 · see citing works
Opportunities and challenges to engineer 3D models of tumor-adaptive immune interactions
Visalakshan, R. M., Lowrey, M. K., Sousa, M. G. C., Helms, H. R., Samiea, A., Schutt, C. E., Moreau, J. M., & Bertassoni, L. E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1162905 · Cited by 31 · see citing works
Abolhassani, H., Eskandari, A., Poor, A. S., Zarrabi, A., Khodadadi, B., Karimifard, S., Sahrayi, H., Bourbour, M., & Yaraki, M. T. (2024) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2024.215754 · Cited by 35 · see citing works
Hot or cold: Bioengineering immune contextures into in vitro patient-derived tumor models
Too, N. S. H., Ho, N. C. W., Adine, C., Iyer, N. G., & Fong, E. L. S. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.001 · Cited by 31 · see citing works
Kalot, R., Mhanna, R., & Talhouk, R. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108156 · Cited by 31 · see citing works
Lugand, L., Mestrallet, G., Laboureur, R., Dumont, C., Bouhidel, F. A., Djouadou, M., Masson-Lecomte, A., Desgrandchamps, F., Culine, S., Carosella, E. D., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.898732 · Cited by 30 · see citing works
Batalha, S., Cristóvão‐Ferreira, S., & Brito, C. (2021) · Cancers · doi:10.3390/cancers13061305 · Cited by 30 · see citing works
Wang, R., Zhang, C., Li, D., & Yao, Y. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.1057913 · Cited by 30 · see citing works
A review of organ-on-chip fabrication methods: From early developments to overcoming inert barriers
Olaizola‐Rodrigo, C., Bayona, C., Oliván, S., & Monge, R. (2025) · iScience · doi:10.1016/j.isci.2025.113992 · Cited by 31 · see citing works
Imaging microphysiological systems: a review
Peel, S. E., & Jackman, M. J. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00186.2020 · Cited by 30 · see citing works
Mediated Electrochemistry to Mimic Biology's Oxidative Assembly of Functional Matrices
Li, J., Kim, E., Gray, K. M., Conrad, C., Tsao, C., Wang, S. P., Zong, G., Scarcelli, G., Stroka, K. M., Wang, L., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202001776 · Cited by 28 · see citing works
Manoharan, T. J. M., Ravi, K., Suresh, A. P., Acharya, A. P., & Nikkhah, M. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202303658 · Cited by 27 · see citing works
PDAC as an immune evasive disease: can 3D model systems aid to tackle this clinical problem?
Narayanan, S., Vicent, S., & Ponz-Sarvisé, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.787249 · Cited by 24 · see citing works
Sánchez-Salazar, M. G., Oliver, R. C.-L., Ramos-Meizoso, S., Jerezano-Flores, V. S., Gallegos-Martínez, S., Bolívar‐Monsalve, E. J., Ceballos‐González, C. F., Santiago, G. T., & Álvarez, M. M. (2023) · Bioengineering · doi:10.3390/bioengineering10050554 · Cited by 23 · see citing works
Mechanoimmunology in the solid tumor microenvironment
Golo, M., Newman, P. L. H., Kempe, D., & Biro, M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20231427 · Cited by 22 · see citing works
Modeling the tumor immune microenvironment for drug discovery using 3D culture
Lee, J. Y., & Chaudhuri, O. (2021) · APL Bioengineering · doi:10.1063/5.0030693 · Cited by 22 · see citing works
Sun, X., Zhang, Z., Zhao, W., Xu, S., Zhang, J., ZhuanSun, X.-M., Ye, J., Han, Y., Gu, Z., & Chen, Z. (2025) · Small · doi:10.1002/smll.202503384 · Cited by 23 · see citing works
Evolution of Metastasis Study Models toward Metastasis‐On‐A‐Chip: The Ultimate Model?
Ruiz‐Espigares, J., Nieto, D., Moroni, L., Jiménez, G., & Marchal, J. A. (2021) · Small · doi:10.1002/smll.202006009 · Cited by 21 · see citing works
Diversity Models and Applications of 3D Breast Tumor-on-a-Chip
Song, K., Zu, X., Du, Z., Hu, Z., Wang, J., & Li, J. (2021) · Micromachines · doi:10.3390/mi12070814 · Cited by 21 · see citing works
3D Tumor Models for Breast Cancer: Whither We Are and What We Need
Balachander, G. M., Kotcherlakota, R., Nayak, B., Kedaria, D., Rangarajan, A., & Chatterjee, K. (2021) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.1c00230 · Cited by 21 · see citing works
Myeloid-derived suppressor cells in cancer
Gao, J., Liu, W., Tang, Z., Fan, J., & Shi, Y. (2022) · iLiver · doi:10.1016/j.iliver.2022.06.002 · Cited by 20 · see citing works
Recent advances in cancer-on-a-chip tissue models to dissect the tumour microenvironment
Seaman, K., Sun, Y., & You, L. (2023) · Med-X · doi:10.1007/s44258-023-00011-1 · Cited by 20 · see citing works
Nieto, D., Jiménez, G., Moroni, L., López‐Ruiz, E., Gálvez‐Martín, P., & Marchal, J. A. (2022) · Medicinal Research Reviews · doi:10.1002/med.21914 · Cited by 18 · see citing works
3D Bioprinting for Tumor Metastasis Research
Lin, M., Tang, M., Duan, W., Xia, S., Liu, W., & Wang, Q. (2022) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.3c00239 · Cited by 19 · see citing works
Long, Y., Shi, H., He, Y., & Qi, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1307228 · Cited by 18 · see citing works
Yang, R., Wang, S., Li, Z., Yin, C., Huang, W., & Huang, W. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217793 · Cited by 19 · see citing works
Shukla, P., Bera, A. K., Ghosh, A. K., Kiranmai, G., & Pati, F. (2024) · Biofabrication · doi:10.1088/1758-5090/ad586b · Cited by 16 · see citing works
Establishment of advanced tumor organoids with emerging innovative technologies
Mao, Y., & Hu, H. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217122 · Cited by 16 · see citing works
Li, Y., Fan, H., Ding, J., Xu, J., Liu, C., & Wang, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.969723 · Cited by 16 · see citing works
Harnessing Tissue Engineering Tools to Interrogate Host-Microbiota Crosstalk in Cancer
Udayasuryan, B., Nguyen, T. T. D., Slade, D. J., & Verbridge, S. S. (2020) · iScience · doi:10.1016/j.isci.2020.101878 · Cited by 15 · see citing works
Tumor spheroid-based microtumor models for preclinical evaluation of anticancer nanomedicines
Khawar, I. A., Ghosh, T., Park, J. K., & Kuh, H. (2021) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-021-00534-y · Cited by 15 · see citing works
Ex vivo modeling of precision immuno-oncology responses in lung cancer
Alsaed, B., Smolander, J., Laitinen, H. K., Lin, L., Bobik, N., Lahtinen, L., Räsänen, M., Jansouz, S., Peltonen, K., Jokinen, E., et al. (2024) · Science Advances · doi:10.1126/sciadv.adq6830 · Cited by 15 · see citing works
Aung, A., Davey, S. K., Theprungsirikul, J., Kumar, V., & Varghese, S. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202201842 · Cited by 15 · see citing works
Self-citationEngineering models of head and neck and oral cancers on-a-chip
Sousa, M. G. D. C., Vignolo, S. M., França, C. M., Mereness, J. A., Fraga, M. A. A., Silva‐Sousa, A. C., Benoit, D. S. W., & Bertassoni, L. E. (2024) · Biomicrofluidics · doi:10.1063/5.0186722 · Cited by 14 · see citing works
Engineering stromal heterogeneity in cancer
Tang, L. J. W., Zaseela, A., Toh, C. C. M., Adine, C., Aydar, A. O., Iyer, N. G., & Fong, E. L. S. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.027 · Cited by 15 · see citing works
Zhang, F., Jozani, K. A., Chakravarty, A., Lin, D. S. Y., Hollinger, A., Rajasekar, S., & Zhang, B. (2025) · Advanced Healthcare Materials · doi:10.1002/adhm.202402946 · Cited by 14 · see citing works
Baka, Z., Stiefel, M., Figarol, A., Godier, C., Mallick, A., Joubert, O., Ashammakhi, N. A., Gaffet, É., & Alem, H. (2022) · Progress in Biomedical Engineering · doi:10.1088/2516-1091/ac8259 · Cited by 13 · see citing works
Sudhakaran, S. V., & Rath, S. N. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-04039-9_13 · Cited by 13 · see citing works
Microphysiological systems as models for immunologically ‘cold’ tumors
Gaebler, D., Hachey, S. J., & Hughes, C. C. W. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1389012 · Cited by 12 · see citing works
Flow‐Induced Vascular Remodeling on‐Chip: Implications for Anti‐VEGF Therapy
Mirzapourshafiyi, F., Huber, E., Karr, L., Tong, J., Bausch, A. R., Simmel, F. C., & Alim, K. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202501416 · Cited by 12 · see citing works
Spatial -omics technologies: the new enterprise in 3D breast cancer models
Pierantoni, L., Reis, R. L., Silva‐Correia, J., Oliveira, J. M., & Heavey, S. (2023) · Trends in biotechnology · doi:10.1016/j.tibtech.2023.07.003 · Cited by 12 · see citing works
Targeted Cancer Therapy‐on‐A‐Chip
Abed, H., Radha, R., Anjum, S., Paul, V., AlSawaftah, N., Pitt, W. G., Ashammakhi, N. A., & Husseini, G. A. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202400833 · Cited by 11 · see citing works
Yoo, S., & Lee, H. J. (2024) · Cells Tissues Organs · doi:10.1159/000541416 · Cited by 13 · see citing works
Advances and Challenges in Human 3D Solid Tumor Models
Natesh, N. R., & Varghese, S. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202419912 · Cited by 13 · see citing works
Self-citationApplications and evolution of 3D cancer-immune cell models
Co, I. L., Fomina, A., Nurse, M., & McGuigan, A. P. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.06.008 · Cited by 10 · see citing works
Recapitulating the Cancer‐Immunity Cycle on a Chip
Lee, Y., Min, J., Kim, S., Park, W., Ko, J., & Jeon, N. L. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202401927 · Cited by 10 · see citing works
Ex Vivo Evaluation of Combination Immunotherapy Using Tumor‐Microenvironment‐on‐Chip
Mu, H., Lin, C., Chu, L., Lin, Y., Li, J., Liu, C., Huang, H., Cheng, S., Lee, T., Lee, H. M., et al. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302268 · Cited by 9 · see citing works
Lizana‐Vasquez, G. D., Ramasubramanian, S., Davarzani, A., Cappabianca, D., Saha, K., Karumbaiah, L., & Torres‐Lugo, M. (2024) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.37823 · Cited by 9 · see citing works
Moresi, F., Noto, F., Vasudevan, J., Bisteau, X., Adriani, G., & Pavesi, A. (2025) · Advanced Therapeutics · doi:10.1002/adtp.202500098 · Cited by 10 · see citing works
Immune microenvironment dynamics of HER2 overexpressing breast cancer under dual anti-HER2 blockade
Batalha, S., Gomes, C. M., & Brito, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1267621 · Cited by 10 · see citing works
Kim, S., Yun, S., Doh, J., & Kim, H. N. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202400475 · Cited by 10 · see citing works
Advancing Tumor Microenvironment Research by Combining Organs-on-Chips and Biosensors
Calejo, I., Heinrich, M. A., Zambito, G., Mezzanotte, L., Prakash, J., & Teixeira, L. M. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-04039-9_7 · Cited by 9 · see citing works
- Authors
- Aung, A., Kumar, V., Theprungsirikul, J., Davey, S. K., & Varghese, S.
- Affiliations
- University of California San Diego (US)
- Duke University (US)
- Corresponding author
- Varghese, Shyni
- Venue
- Cancer Research
- Published
- 2020-01-15
- Volume
- 80
- Issue
- 2
- Pages
- 263-275
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC8545579
- OpenAlex
- W2991421324
- Cited by
- 146
- References
- 50
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 27 · 2023: 22 · 2022: 28 · 2021: 22 · 2020: 14
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NHLBI (T32 HL 105373)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- tumor-on-a-chip, breast cancer, T cell recruitment, tumor microenvironment, tumor-immune interactions, monocytes, endothelial cells, gelatin hydrogel, chemokines, hypoxia, tumor spheroids, endothelial permeability, tumor cell migration
- MeSH terms
- Proof of Concept Study, Breast Neoplasms, Cell Communication, Feasibility Studies, Female, Humans, Lymphocyte Activation, Monocytes, T-Lymphocytes, Cell Hypoxia, Spheroids, Cellular, Chemokines, Cell Culture Techniques, Hydrogels, Cell Line, Tumor, Lab-On-A-Chip Devices, Tumor Microenvironment, Cell Engineering, Human Umbilical Vein Endothelial Cells
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